The blog will remain accessible for the time being, in case anything from the past months will help someone in their research. One reason for starting this was to be a resource for indivduals studying or working in the fields, and I’d like it to stay that way (as Sam Zemurray, the banana king, said, “There is no problem you can’t solve if you understand your business from A to Z”.)

As always, please feel free to reach out with any questions, comments, or otherwise (social media can be found on a previous post here). Enjoy the read.

-EDM

Top papers of the week

Proc Natl Acad Sci U S A: Direct neuronal conversion of microglia/macrophages reinstates neurological function after stroke (link)

Although generating new neurons in the ischemic injured brain would be an ideal approach to replenish the lost neurons for repairing the damage, the adult mammalian brain retains only limited neurogenic capability. Here, we show that direct conversion of microglia/macrophages into neurons in the brain has great potential as a therapeutic strategy for ischemic brain injury. After transient middle cerebral artery occlusion in adult mice, microglia/macrophages converge at the lesion core of the striatum, where neuronal loss is prominent. Targeted expression of a neurogenic transcription factor, NeuroD1, in microglia/macrophages in the injured striatum enables their conversion into induced neuronal cells that functionally integrate into the existing neuronal circuits. Furthermore, NeuroD1-mediated induced neuronal cell generation significantly improves neurological function in the mouse stroke model, and ablation of these cells abolishes the gained functional recovery. Our findings thus demonstrate that neuronal conversion contributes directly to functional recovery after stroke.

Aging Cell: Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study (link)

The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear. We performed high-depth RNA-Seq (387-618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12- and 24-month follow-up from the 90 CALERIE participants randomized to CR and "ad libitum" control. Using linear mixed effect model, we identified protein-coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation. Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans.

Adv Healthc Mater: 4-Axis 3D Printed Tubular Biomaterials Imitating the Anisotropic Nanofiber Orientation of Porcine Aortae (link)

Many of the peculiar properties of the vasculature are related to the arrangement of anisotropic proteinaceous fibers in vessel walls. Understanding and imitating these arrangements can potentially lead to new therapies for cardiovascular diseases. These can be pre-surgical planning, for which patient specific ex vivo anatomical models for endograft testing are of interest. Alternatively, therapies can be based on tissue engineering, for which degradable in vitro cell growth substrates are used to culture replacement parts. In both cases materials are desirable that imitate the biophysical properties of vessels, including their tubular shapes and compliance. This work contributes to these demands by offering methods for the manufacturing of anisotropic 3D printed nanofibrous tubular structures that have similar biophysical properties as porcine aortae, that are biocompatible, and that allow for a controlled nutrient diffusion. Tubes of various sizes with axial, radial or alternating nanofiber orientation along the blood flow direction are manufactured by a customized method. Blood pressure resistant, compliant, stable and cell culture compatible structures are obtained, that can be degraded in vitro on demand. It is suggested that these healthcare materials can contribute to the next generation of cardiovascular therapies of ex vivo pre-surgical planning or in vitro cell culture.

Stem cells / RegenMed

• Publications:

  • Mol Ther: Transplanted Human Neural Stem Cells Rescue Phenotypes in zQ175 Huntington's Disease Mice and Innervate the Striatum (link)

  • BMC Med Ethics: Patients accept therapy using embryonic stem cells for Parkinson's disease: a discrete choice experiment (link)

  • Sci Transl Med: Regeneration of neuromuscular synapses after acute and chronic denervation by inhibiting the gerozyme 15-prostaglandin dehydrogenase (link)

  • Small: Dual siRNA-Loaded Cell Membrane Functionalized Matrix Facilitates Bone Regeneration with Angiogenesis and Neurogenesis (link)

  • Tissue Eng Regen Med: MiRNA320a Inhibitor-Loaded PLGA-PLL-PEG Nanoparticles Contribute to Bone Regeneration in Trauma-Induced Osteonecrosis Model of the Femoral Head (link)

  • Stem Cell Rev Rep: Pineal Gland Hormone Melatonin Inhibits Migration of Hematopoietic Stem/Progenitor Cells (HSPCs) by Downregulating Nlrp3 Inflammasome and Upregulating Heme Oxygenase-1 (HO-1) Activity (link)

  • Tissue Eng Part B Rev: Ex vivo Peptide Decoration Strategies on Stem Cell Surfaces for Augmenting Endothelium Interaction (link)

  • Nat Commun: Multi-species atlas resolves an axolotl limb development and regeneration paradox (link)

• Reviews:

  • Acta Biomater: Immunomodulatory Functions of Microorganisms in Tissue Regenerative Healing (link)

  • Blood Adv: Blood stem cell grafts: frozen is fine, but fresh is best (link)

  • Cell Prolif: Technical specifications for ethics review of human stem cell research (link)

Aging / Longevity

• Translational:

  • Proc Natl Acad Sci U S A: Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration in Psen mutant mice (link)

  • Nature: Apoptotic stress causes mtDNA release during senescence and drives the SASP (link)

• Organ- and disease-specific:

  • JAMA Neurol: Tau Oligomer-Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease (link)

  • J Gerontol A Biol Sci Med Sci: Altered gene expression within the renin-angiotensin system in normal ageing and dementia (link)

  • Alzheimers Dement: Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (link)

  • J Intern Med: Epigenetic clocks indicate that kidney transplantation and not dialysis mitigate the effects of renal ageing (link)

• Other:

  • BMC Geriatr: The roots of healthy aging: investigating the link between early-life and childhood experiences and later-life health (link)

  • J Am Geriatr Soc: Serum total tau, neurofilament light, and glial fibrillary acidic protein are associated with mortality in a population study (link)

  • Psychol Aging: Long-term aging trajectories of the accumulation of disease burden as predictors of daily affect dynamics and stressor reactivity (link)

• Reviews:

  • EMBO Rep: Lysosomes in senescence and aging (link)

  • Aging Cell: The role of cardiac resident macrophage in cardiac aging (link)

  • Arch Physiol Biochem: Intermittent fasting in health and disease (link)

  • Ageing Res Rev: Therapeutic efficacy and promise of stem cell-derived extracellular vesicles in Alzheimer's disease and other aging-related disorders (link)

Model systems / Protocols

• Models:

  • Cell Prolif: The efficient generation of functional human hepatocytes from chemically induced pluripotent stem cells (link)

  • Biomed Mater: Fabrication of shape-designable cartilage from human induced pluripotent stem cell-derived chondroprogenitors using a cell self-aggregation technique (link)

  • Stem Cell Res Ther: Vascular organoids: unveiling advantages, applications, challenges, and disease modelling strategies (link)

• Translational:

  • J Neuroinflammation: Human iPSC-derived glia models for the study of neuroinflammation (link)

  • Cell Rep: Probing cerebral malaria inflammation in 3D human brain microvessels (link)

  • PLoS One: On the utilization of the induced pluripotent stem cell (iPSC) model to study substance use disorders: A scoping review protocol (link)

  • Cell Prolif: Integration of human organoids single-cell transcriptomic profiles and human genetics repurposes critical cell type-specific drug targets for severe COVID-19 (link)

  • Hum Reprod: Human-induced pluripotent stem cell-derived ovarian support cell co-culture improves oocyte maturation invitro after abbreviated gonadotropin stimulation (link)

  • Handb Exp Pharmacol: Using Human iPSC-Derived Peripheral Nervous System Disease Models for Drug Discovery (link)

• Biomaterials:

  • Nat Biomed Eng: Laminin-coated electronic scaffolds with vascular topography for tracking and promoting the migration of brain cells after injury (link)

  • Small: Bio-electrospraying 3-D Organotypic Human Skin Cultures (link)

  • Regen Med: Electrospun aligned tacrolimus-loaded polycaprolactone biomaterials for peripheral nerve repair (link)

  • Small: Accelerating Patterned Vascularization Using Granular Hydrogel Scaffolds and Surgical Micropuncture (link)

Clinical

• Publications:

  • Int J Low Extrem Wounds: The Therapeutic Efficacy of Freeze-Dried Human Amniotic Membrane Allograft Gel for Diabetic Foot Ulcers: A Phase-1 Clinical Trial (link)

• Corporate:

  • Athersys: Athersys Reports Interim Analysis Results of MASTERS-2 Clinical Study with MultiStem in Ischemic Stroke, Signs Memorandum of Understanding (MOU) for Global ARDS License with Healios (link)

  • BioCardia: BioCardia Announces Completion of Enrollment in Phase III CardiAMP HF Trial and Plans for CardiAMP HF Trial II (link)

  • Sana Biotech: Sana Biotechnology Announces Increased Focus on Hypoimmune-Related Pipeline with the Potential to Deliver Clinical Proof of Concept Data from Four Programs in 2023 and 2024 with a 2024 Operating Burn under $200M (link)

• Newly posted studies:

  • NCT06072794: A Proof of Concept Study to Evaluate Exosomes From Human Mesenchymal Stem Cells in Women With Premature Ovarian Insufficiency (POI) (VL-POI-01) (link)

  • NCT06073808: The Role of Amnion Membrane Allografts in Nipple Preservation (AmnioFix) (link)

  • NCT06075706: Trial of Efficacy and Safety of MC0518 Versus Best Available Therapy in Participants With Steroid-Refractory Acute Graft Versus Host Disease (BALDER) (link)

  • NCT06078072: Biomaterials and Mesenchymal Stem/​Stromal Cells in the Treatment of Knee Articular Surface Lesions (link)

  • NCT06078059: Mechanisms of Treatment Effects Using Cultured, Allogeneic Mesenchymal Stromal Stem Cells (MSCs) in Knee Osteoarthritis (link)

Other (Articles, Perspectives, etc.)

• WSJ: The FDA’s Laboratory Land Grab (link)

• WSJ: The Secret to Living to 100? It’s Not Good Habits (link)

• Nature: AI’s potential to accelerate drug discovery needs a reality check (link)

• Business:

  • Applied StemCell: QHP Capital Acquires Applied StemCell (link)

  • Bayer: Bayer Opens First Cell Therapy Manufacturing Facility to Advance Regenerative Medicines on a Global Scale (link)

• Other interesting papers:

  • J Youth Adolesc: Reciprocal Associations Between Science Efficacy, STEM Identity and Scientist Career Interest Among Adolescent Girls within the Context of Informal Science Learning (link)

  • Science: A family portrait of human brain cells (link)

I was wondering about the use of large data in disease targeting when Endpoints produced this timely article linking to multiple papers answering that exact question. There are three (here, here, here) which seem to be part of a broader effort by Nature this week to publish a lot of genomics biomarker work. The most important one in my mind is the first (“Plasma proteomic associations with genetics and health in the UK Biobank”), which includes 13(!) different biotech and pharma companies coming together to publish this new analysis. It is worth mentioning all of them so you understand the scope:

Alnylam (Alnylam Human Genetics); AstraZeneca (AstraZeneca Genomics Initiative); Biogen (Biogen Biobank Team); BMS (Bristol Myers Squibb); Roche (Genentech Human Genetics); GSK (GlaxoSmithKline Genomic Sciences); Pfizer (Pfizer Integrative Biology); J&J (Population Analytics of Janssen Data Sciences); Regeneron (Regeneron Genetics Center); Novo Nordisk (Human Genetics Centre of Excellence); Amgen (Amgen Research); Takeda (Data Science Institute); and Calico (Calico Life Sciences)
*some companies have multiple teams and representatives

I like these papers particularly because it hearkens back to the “good old days” of brute-forcing one’s way through a vast array of data. For all the “AI drug discovery” companies out there, few have been able to replicate the success of the classic high throughput screens and Lipinski’s Rule of Five (a bit dated but you get my drift). It’s just nice to see the use of huge, publicly available data sets to uncover literally thousands of new targets in multiple diseases. The fun part too is imagining these pharma companies going back to the labs and thoroughly enjoying testing the applicability and druggability of these new targets; I’ll be looking for the follow up pubs in a few years.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Cell Stem Cell: Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy (link)

Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons. Single-dose intrahippocampal delivery of the interneurons in a mouse model of chronic MTLE resulted in consistent mesiotemporal seizure suppression, with most animals becoming seizure-free and surviving longer. The grafted interneurons dispersed locally, functionally integrated, persisted long term, and significantly reduced dentate granule cell dispersion, a pathological hallmark of MTLE. These disease-modifying effects were dose-dependent, with a broad therapeutic range. No adverse effects were observed. These findings support an ongoing phase 1/2 clinical trial (NCT05135091) for drug-resistant MTLE.

J Am Soc Nephrol: Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM) (link)

Background: Systemic therapy with mesenchymal stromal cells may target maladaptive processes involved in diabetic kidney disease progression. However, clinical translation of this approach has been limited.

Methods: The Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study, a randomized, placebo-controlled phase 1b/2a trial, assesses safety, tolerability, and preliminary efficacy of next-generation bone marrow-derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) in adults with type 2 diabetes and progressive diabetic kidney disease. This first, lowest dose cohort of 16 participants at three European sites was randomized (3:1) to receive intravenous infusion of ORBCEL-M (80×10 6 cells, n =12) or placebo ( n =4) and was followed for 18 months.

Results: At baseline, all participants were negative for anti-HLA antibodies and the measured GFR (mGFR) and estimated GFR were comparable between groups. The intervention was safe and well-tolerated. One placebo-treated participant had a quickly resolved infusion reaction (bronchospasm), with no subsequent treatment-related serious adverse events. Two ORBCEL-M recipients died during follow-up of causes deemed unrelated to the trial intervention; one recipient developed low-level anti-HLA antibodies. The median annual rate of kidney function decline after ORBCEL-M therapy compared with placebo did not differ by mGFR, but was significantly lower by eGFR estimated by the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Immunologic profiling provided evidence of preservation of circulating regulatory T cells, lower natural killer T cells, and stabilization of inflammatory monocyte subsets in those receiving the cell therapy compared with placebo.

Conclusions: Findings indicate safety and tolerability of intravenous ORBCEL-M cell therapy in the trial's lowest dose cohort. The rate of decline in eGFR (but not mGFR) over 18 months was significantly lower among those receiving cell therapy compared with placebo. Further studies will be needed to determine the therapy's effect on CKD progression. .

Sci Transl Med: Multicellular bioprinted skin facilitates human-like skin architecture in vivo (link)

Bioprinting is a promising alternative method to generate skin substitutes because it can replicate the structural organization of the skin into biomimetic layers in vitro. In this study, six primary human skin cell types were used to bioprint a trilayer skin construct consisting of epidermis, dermis, and hypodermis. Transplantation of the bioprinted skin with human cells onto full-thickness wounds of nu/nu mice promoted rapid vascularization and formation of epidermal rete ridges analogous to the native human epidermis, with a normal-looking extracellular matrix. Cell-specific staining confirmed the integration of the implanted cells into the regenerated skin. Using a similar approach, a 5 centimeter-by-5 centimeter bioprinted autologous porcine skin graft was transplanted onto full-thickness wounds in a porcine excisional wound model. The bioprinted skin graft improved epithelialization, reduced skin contraction, and supported normal collagen organization with reduced fibrosis. Differential gene expression demonstrated pro-remodeling protease activity in wounds transplanted with bioprinted autologous skin grafts. These results demonstrate that bioprinted skin can support skin regeneration to allow for nonfibrotic wound healing and suggest that the skin bioprinting technology may be applicable for human clinical use.

Stem cells / RegenMed

• Publications:

  • Nat Commun: Mechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy (link)

  • Eur Heart J: Intracoronary delivery of extracellular vesicles from human cardiac progenitor cells reduces infarct size in porcine acute myocardial infarction (link)

  • Tissue Eng Regen Med: Delivery of SAV-siRNA via Exosomes from Adipose-Derived Stem Cells for the Treatment of Myocardial Infarction (link)

  • Stem Cell Res Ther: Impaired immunosuppressive effect of bone marrow mesenchymal stem cell-derived exosomes on T cells in aplastic anemia (link)

  • Exp Mol Med: Vascular regeneration and skeletal muscle repair induced by long-term exposure to SDF-1α derived from engineered mesenchymal stem cells after hindlimb ischemia (link)

  • Cell Stem Cell: Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson’s disease, STEM-PD (link)

  • Transl Stroke Res: Mesenchymal Stem Cells Overexpressing FGF21 Preserve Blood-Brain Barrier Integrity in Experimental Ischemic Stroke (link)

  • Stem Cells Transl Med: Human Neural Progenitors Expressing GDNF Enhance Retinal Protection in a Rodent Model of Retinal Degeneration (link)

  • Bone Joint Res: Regeneration of injured articular cartilage using the recombinant human amelogenin protein (link)

  • J Nanobiotechnology: Cerium oxide nanoparticles-carrying human umbilical cord mesenchymal stem cells counteract oxidative damage and facilitate tendon regeneration (link)

  • Stem Cell Res Ther: Subconjunctival injection of human umbilical cord mesenchymal stem cells alleviates experimental allergic conjunctivitis via regulating T cell response (link)

  • Inflamm Regen: Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis (link)

  • Am J Respir Crit Care Med: Intravenous Autologous Bone-Marrow-derived Mesenchymal Stromal Cells Delay Acute Respiratory Distress Syndrome in Swine (link)

• Reviews:

  • Regen Med: Peripheral nerve regeneration: a challenge far from being overcome (link)

  • Nat Rev Endocrinol: Stem cell-derived islet therapy: is this the end of the beginning? (link)

  • Biomater Sci: Engineered exosomes for tissue regeneration: from biouptake, functionalization and biosafety to applications (link)

  • Neurosci Bull: Stem Cell-Based Hair Cell Regeneration and Therapy in the Inner Ear (link)

Aging / Longevity

• Translational:

  • Nat Aging: In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation (link)

  • Sci Rep: Lactobacillus paracasei HII01 enhances lifespan and promotes neuroprotection in Caenorhabditis elegans (link)

• Organ- and disease-specific:

  • Nat Aging: SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B (link)

  • Biogerontology: The influence of biological sex in human skeletal muscle transcriptome during ageing (link)

  • Aging (Albany NY): Reduction of double-strand DNA break repair exacerbates vascular aging (link)

  • ACS Nano: Nanotopographical Cues Tune the Therapeutic Potential of Extracellular Vesicles for the Treatment of Aged Skeletal Muscle Injuries (link)

• Other:

  • J Gerontol A Biol Sci Med Sci: Beyond inflammaging: The Impact of Immune System Aging on Age-Related Muscle Decline, results from the InCHIANTI study (link)

  • Alzheimers Dement (Amst): Olfactory function, neurofilament light chain, and cognitive trajectory: A 12-year follow-up of the Shanghai Aging Study (link)

  • BMC Public Health: Association between daily alcohol consumption and serum alpha klotho levels among U.S. adults over 40 years old: a cross-sectional study (link)

  • Netw Neurosci: Functional connectome fingerprinting across the lifespan (link)

• Reviews:

  • Nat Aging: Combinatorial interventions in aging (link)

  • Development: Development, regeneration and aging: a bizarre love triangle (link)

  • N Engl J Med: Stem-Cell Aging and Pathways to Precancer Evolution (link)

  • Cold Spring Harb Perspect Med: Mitochondrial Targeted Interventions for Aging (link)

Model systems / Protocols

• Models:

  • Curr Protoc: Current Strategies of Modeling Human Trophoblast Using Human Pluripotent Stem Cells in vitro (link)

  • Development: Human pluripotent stem cells-derived inner ear organoids recapitulate otic development in vitro (link)

  • Dev Neurobiol: Preparation of astrocytes by directed differentiation of pluripotent stem cells and somatic cell transdifferentiation (link)

  • Development: Mapping oto-pharyngeal development in a human inner ear organoid model (link)

• Biomaterials:

  • Adv Healthc Mater: Adipose-derived Stromal Cells Preserve Pancreatic Islet Function in A Transplantable 3d Bioprinted Scaffold (link)

  • ACS Nano: Ammonium Persulfate-Loaded Carboxylic Gelatin-Methacrylate Nanoparticles Promote Cardiac Repair by Activating Epicardial Epithelial-Mesenchymal Transition via Autophagy and the mTOR Pathway (link)

  • ACS Nano: Enhanced Neuron Growth and Electrical Activity by a Supramolecular Netrin-1 Mimetic Nanofiber (link)

  • Acta Biomater: Bioactive and chemically defined hydrogels with tunable stiffness guide cerebral organoid formation and modulate multi-omics plasticity in cerebral organoids (link)

  • Small: Bone-Targeted Biomimetic Nanogels Re-Establish Osteoblast/Osteoclast Balance to Treat Postmenopausal Osteoporosis (link)

  • Adv Healthc Mater: Injectable Bioactive Antioxidative One-component Polycitrate Hydrogel with Anti-inflammatory Effects for Osteoarthritis Alleviation and Cartilage Protection (link)

  • ACS Appl Mater Interfaces: Biofabrication of Composite Tendon Constructs with the Fibrous Arrangement, High Cell Density, and Enhanced Cell Alignment (link)

Clinical

• Publications:

  • Stem Cell Res Ther: Adipose-derived, autologous mesenchymal stem cell therapy for patients with post-COVID-19 syndrome: an intermediate-size expanded access program (link)

  • Lancet Haematol: Allogeneic haematopoietic stem-cell transplantation versus gene therapy for haemoglobinopathies (link)

  • Geroscience: Blazing a trail for the clinical use of rapamycin as a geroprotecTOR (link)

• Newly posted studies:

  • NCT06066827: Hair Regeneration in Androgenetic Alopecia (link)

  • NCT06065189: Base-edited Autologous Hematopoietic Stem Cell Transplantation in Treating Patients With β-thalassemia Major (link)

  • NCT06071143: Safety and Efficacy of KDSTEM Inj. in Patients With Chronic Kidney Disease (link)

Other (Articles, Perspectives, etc.)

• Nobel Prize: The Nobel Assembly at Karolinska Institutet has today decided to award the 2023 Nobel Prize in Physiology or Medicine jointly to Katalin Karikó and Drew Weissman for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19 (link)

• Business:

  • Precede Biosciences: Precede Biosciences Emerges from Stealth to Dramatically Impact Precision Medicine with a First-in-Class Liquid Biopsy Platform (link)

  • Lexeo: Genetic medicines developer Lexeo Therapeutics files for IPO (link)

  • TechCrunch: Pow.Bio announces its Series A round and plans for an upcoming demo facility to make high efficiency fermentation more accessible (link)

  • Regen Med: Safety and efficacy claims made by US businesses marketing purported stem cell treatments and exosome therapies (link)

• Other interesting papers:

  • JAMA Pediatr: Persistence of Autism Spectrum Disorder From Early Childhood Through School Age (link)

  • Sci Rep: Identifying potential biomarkers of idiopathic pulmonary fibrosis through machine learning analysis (link)

  • BMC Med Res Methodol: Sequential regression and simulation: a method for estimating causal effects from heterogeneous clinical trials without a common control group (link)

  • Nature: The status of the human gene catalogue (link)

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Sci Rep: Modelling lifespan reduction in an exogenous damage model of generic disease (link)

We model the effects of disease and other exogenous damage during human aging. Even when the exogenous damage is repaired at the end of acute disease, propagated secondary damage remains. We consider both short-term mortality effects due to (acute) exogenous damage and long-term mortality effects due to propagated damage within the context of a generic network model (GNM) of individual aging that simulates a U.S. population. Across a wide range of disease durations and severities we find that while excess short-term mortality is highest for the oldest individuals, the long-term years of life lost are highest for the youngest individuals. These appear to be universal effects of human disease. We support this conclusion with a phenomenological model coupling damage and mortality. Our results are consistent with previous lifetime mortality studies of atom bomb survivors and post-recovery health studies of COVID-19. We suggest that short-term health impact studies could complement lifetime mortality studies to better characterize the lifetime impacts of disease on both individuals and populations.

Adv Healthc Mater: A Bioresorbable and Conductive Scaffold Integrating Silicon Membranes for Peripheral Nerve Regeneration (link)

Peripheral nerve injury represents one of the most common types of traumatic damage, severely impairing motor and sensory functions, and posttraumatic nerve regeneration remains a major challenge. Electrical cues are critical bioactive factors that promote nerve regrowth, and bioartificial scaffolds incorporating conductive materials to enhance the endogenous electrical field have been demonstrated to be effective. The utilization of fully biodegradable scaffolds can eliminate material residues, avoid the need for a second surgery and circumvent the need for secondary retrieval procedures. Here, we propose a fully bioresorbable and conductive nerve scaffold integrating N-type silicon (Si) membranes, which can deliver both structural guidance and electrical cues for the repair of nerve defects. The entire scaffold is fully biodegradable, and the introduction of N-type Si can significantly promote the proliferation and production of neurotrophic factors in Schwann cells and enhance the calcium activity of dorsal root ganglion (DRG) neurons. The conductive scaffolds enable accelerated nerve regeneration and motor functional recovery in rodents with sciatic nerve transection injuries. This work sheds light on the advancement of bioresorbable and electrically active materials to achieve desirable neural interfaces and improved therapeutic outcomes, offering essential strategies for regenerative medicine.

Nature: Inhibition of fatty acid oxidation enables heart regeneration in adult mice (link)

Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5. Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.

Cell Rep Methods: Three-dimensional molecular cartography of human cerebral organoids revealed by double-barcoded spatial transcriptomics (link)

Spatially resolved transcriptomics is revolutionizing our understanding of complex tissues, but scaling these approaches to multiple tissue sections and three-dimensional tissue reconstruction remains challenging and cost prohibitive. In this work, we present a low-cost strategy for manufacturing molecularly double-barcoded DNA arrays, enabling large-scale spatially resolved transcriptomics studies. We applied this technique to spatially resolve gene expression in several human brain organoids, including the reconstruction of a three-dimensional view from multiple consecutive sections, revealing gene expression heterogeneity throughout the tissue.

Stem cells / RegenMed

• Stem Cell Res Ther: Human osteoarthritic articular cartilage stem cells suppress osteoclasts and improve subchondral bone remodeling in experimental knee osteoarthritis partially by releasing TNFAIP3 (link)

• Bone Res: Loss of Notch signaling in skeletal stem cells enhances bone formation with aging (link)

• Aging (Albany NY): M2 macrophage-derived exosomal miR-486-5p influences the differentiation potential of bone marrow mesenchymal stem cells and osteoporosis (link)

• J Transl Med: GMP-grade human neural progenitors delivered subretinally protect vision in rat model of retinal degeneration and survive in minipigs (link)

• Stem Cell Res Ther: Human umbilical cord mesenchymal stem cells ameliorate colon inflammation via modulation of gut microbiota-SCFAs-immune axis (link)

• Tissue Eng Part C Methods: Transplantation of iPSC-derived airway epithelia with a collagen scaffold into the nasal cavity (link)

• Transfusion: HLA-haplotype redundancy and rareness in Canadian Blood Services' Stem Cell Registry and Cord Blood Bank: Novel metrics for optimizing utility (link)

• Reviews:

  • Regen Med: Therapeutic potential of adipose tissue derivatives in skin photoaging (link)

  • Stem Cell Rev Rep: Application of Induced Pluripotent Stem Cells in Malignant Solid Tumors (link)

  • Inflamm Res: Kinins: Locally formed peptides during inflammation with potential use in tissue regeneration (link)

  • Transplantation: Legal and Regulatory Challenges for Emerging Regenerative Medicine Solutions for Diabetes (link)

Aging / Longevity

• Organ- and disease-specific:

  • Aging Cell: Senolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis (link)

  • J Immunol: B Cells from Aged Mice Do Not Have Intrinsic Defects in Affinity Maturation in Response to Immunization (link)

  • Aging Cell: Cellular and molecular evidence that synaptic Schwann cells contribute to aging of mouse neuromuscular junctions (link)

• Other:

  • Geroscience: Sex differences in biological aging and the association with clinical measures in older adults (link)

  • Sci Data: Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity (link)

  • Elife: Status and physiological significance of circulating adiponectin in the very old and centenarians: an observational study (link)

• Reviews:

  • J Mol Med (Berl): Potential role of mesenchymal stem cells in T cell aging (link)

Model systems / Protocols

• Models:

  • Dev Cell: Generation and molecular characterization of human pluripotent stem cell-derived pharyngeal foregut endoderm (link)

  • Cell Rep Methods: Reliable multiplex generation of pooled induced pluripotent stem cells (link)

  • Nat Protoc: Generation of proximal tubule-enhanced kidney organoids from human pluripotent stem cells (link)

  • PLoS One: Microglia-secreted TNF-α affects differentiation efficiency and viability of pluripotent stem cell-derived human dopaminergic precursors (link)

  • Cell Prolif: General requirements for the production of extracellular vesicles derived from human stem cells (link)

• Translational:

  • Nature: Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment (link)

• Biomaterials:

  • Nanoscale: Low-power microwaves: a cell-compatible physical treatment to enhance the mechanical properties of self-assembling peptides (link)

  • Biofabrication: Bioinspired 3D-printed scaffold embedding DDAB-nano ZnO/nanofibrous microspheres for regenerative diabetic wound healing (link)

  • ACS Appl Mater Interfaces: Encapsulation of Human Spinal Cord Progenitor Cells in Hyaluronan-Gelatin Hydrogel for Spinal Cord Injury Treatment (link)

  • Sci Adv: Inversely engineered biomimetic flexible network scaffolds for soft tissue regeneration (link)

  • Adv Healthc Mater: Biomimetic Structural Protein Based Magnetic Responsive Scaffold for Enhancing Bone Regeneration by Physical Stimulation on Intracellular Calcium Homeostasis (link)

  • Nanomedicine (Lond): Self-assembling peptide RADA16: a promising scaffold for tissue engineering and regenerative medicine (link)

  • Small: Antimicrobial Hydrogels: Potential Materials for Medical Application (link)

Clinical

• Pubs:

  • J Dermatol: Efficacy of autologous dermal sheath cup cell transplantation in male and female pattern hair loss: A Single-Arm, Multi-Center, phase III equivalent clinical study (link)

  • J Cereb Blood Flow Metab: Randomized placebo-controlled trial of CL2020, an allogenic muse cell-based product, in subacute ischemic stroke (link)

  • J Neurol Neurosurg Psychiatry: Haematopoietic stem cell transplantation for treatment of relapsing-remitting multiple sclerosis in Sweden: an observational cohort study (link)

  • Orthop Surg: One Step Double Augmentation with Human Dermis Allograft and Homologous PRP in Misdiagnosed and or Chronic Achilles Tendon Ruptures (link)

  • Hematol Oncol: Comparison of autologous, matched sibling, and alternative donor stem cell transplant outcomes for acute myeloid leukemia patients in first remission: A propensity score matching study (link)

• Corporate:

  • Gamida Cell: First Patient Receives Gamida Cell's Omisirge™ (omidubicel-onlv) (link)

  • Brainstorm Cell Therapeutics: BrainStorm Cell Therapeutics Provides Update on FDA Advisory Committee Meeting to Review NurOwn for the Treatment of ALS (link)

• Newly posted studies:

  • NCT06051747: Patient-Customized Bioprinting Technology for Practical Regeneration of the Respiratory Tract (Trachea) (link)

  • NCT06058078: RY_SW01 Cell Injection Therapy in Active Lupus Nephritis (link)

Other (Articles, Perspectives, etc.)

• Endpoints: In the race to get type 1 patients off insulin, focus turns to cell transplants and insulin-producing stem cells (link)

• Business:

  • CellFE: Exclusive: CellFE raises $22M Series A to advance a new cell therapy manufacturing idea (link)

  • Thymmune Therapeutics: Biden-Harris Administration announces funding for regenerative tissue project to restore immune system function and improve health outcomes through ARPA-H award (link)

  • Endpoints: Despite a summer of blockbuster rounds, biotech funding is on track to level off at pre-pandemic norms (link)

  • JAMA Netw Open: Changes in Diagnoses and Site of Care for Patients Receiving Hospice Care From Agencies Acquired by Private Equity Firms and Publicly Traded Companies (link)

• Other interesting papers:

  • Nat Biotechnol: Single-cell lineage capture across genomic modalities with CellTag-multi reveals fate-specific gene regulatory changes (link)

  • Nature: Spatial atlas of the mouse central nervous system at molecular resolution (link)

  • Lancet Diabetes Endocrinol: Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) (link)

To start, you can find me on LinkedIn and Twitter (feel free to say hello!). I’ve used these platforms (specifically Twitter) since grad school to help learn about the business of science and to talk with like-minded individuals more advanced in their careers. This came out of a desire to not want to be in the lab for numerous additional years (post-doc, Sr Scientist, Lab Head, PI, etc.), though that desire was not borne out of hatred of my thesis work.

In grad school at the Univ of Delaware, I focused on cardiac regeneration using stem cells and nanomedicine. The work was appealing because it was truly translational - I wanted to see if the techniques worked in vivo, not just report on dish-level differentiations. We started by differentiating human bone marrow mesenchymal stem cells towards the cardiac lineage, optimized following numerous test mixtures of peptides and small molecules. This mixture of cells and factors was overlayed on a vertically aligned nanofiber scaffolding matrix (to mimic the orientation of cardiac tissue) and the growth and differentiation was characterized.

The translational step was inducing heart attacks in rats, waiting for damage to set in (confirmed via echocardiograph), then injecting the scaffolding / cells / factors mixture to (hopefully!) induce cardiac repair. Spending 12hrs a day in an animal facility for 4mo in a thesis make-or-break experiment was…stressful…but ultimately we showed that cardiac repair could be induced following ‘low’ and ‘high’ (but not ‘very low’ or ‘medium’) levels of cardiac damage. The conclusion was that more secreted elements helped repair the ‘low’ damage (‘secretions’ were probably exosomes), while the ‘high’ damage was repaired by actual cell and scaffold engraftment (confirmed via tissue staining methods). The ‘very low’ damage hearts spontaneously improved, while the ‘medium’ damage saw no cell engraftment but was likely too damaged for ‘secreted factors’. Repaired hearts were not back to normal, but were significantly improved vs controls.

So that’s the two-paragraph elevator pitch on my thesis, and of course it took years for that process to play out. You’ll find a few of these methods and interim results published, but unfortunately the full work for various reasons was never published as a journal article. I was successfully able to transition to industry following my defense, and have been happily ensconced in the business of science ever since.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Exp Dermatol: A 2-week time-restricted feeding attenuates psoriasis-like lesions with reduced inflammatory cytokines and immunosenescence in mice (link)

Psoriasis, a well-established T-cell mediated dermatosis, exhibits a robust correlation with obesity and systemic inflammation, manifesting psoriasis skin lesions and premature immunosenescence within the peripheral blood and lesion. Intermittent fasting (IF) has exhibited various beneficial effects in reducing inflammation, resisting oxidative stress and slowing ageing, as well as losing weight. A form of IF known as time-restricted feeding (TRF) restricts daily caloric intake within 4-8 h. Nonetheless, the advantageous impacts of TRF on psoriasis still require further verification. We measured the acanthosis in Imiquimod (IMQ)-induced psoriasis mice and evaluated their pathological phenotypes. Our study examined the effects of a 2-week TRF on body weight and metabolic parameters. The subsets of T cells in spleens and skin lesions were accessed by flow cytometry. Cytokines and senescence-associated genes were evaluated by immunofluorescence and RT-qPCR. RNA sequencing was conducted on skin lesions. According to our findings, a 2-week TRF attenuates psoriasis-like lesions in mice with reduced inflammatory cytokines and mitigated immunosenescence. TRF increased the counts of CD4+ Treg cells in skin lesions while reducing the counts of Th2 and Th17 cells in spleens. Furthermore, the administration of TRF resulted in a decrease in the population of CD4+ senescent T cells in both the dermis and spleens, concomitant with the expression of senescence-associated genes in spleen CD4+ T cells. The outcomes mentioned above provide valuable evidence in support of TRF for the management of psoriasis.

Nat Commun: Nongenetic surface engineering of mesenchymal stromal cells with polyvalent antibodies to enhance targeting efficiency (link)

Systemic infusion is a prevalent administration method for mesenchymal stromal cells (MSCs) in clinical trials. However, the inability to deliver a large number of therapeutic cells to diseased tissue is a substantial barrier. Here, we demonstrate that surface engineering of MSCs with polyvalent antibodies can effectively improve the targeting efficiency of MSCs to diseased tissue. The polyvalent antibody is directly synthesized on the cell surface via DNA template-directed biomolecule assembly. The data show that engineered MSCs exhibit superior adhesion to inflamed endothelium in vitro and in vivo. In female mouse models of acute inflammation and inflammatory bowel disease, engineered MSCs show enhanced targeting efficiency and therapeutic efficacy in damaged tissues. Notably, the entire procedure for polyvalent functionalization only requires the simple mixing of cells and solutions under physiological conditions within a few hours, which significantly reduces preparation processes and manufacturing costs and minimizes the impact on the cells. Thus, our study provides a strategy for improved MSC-based regenerative medicine.

PLoS Genet: Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans (link)

mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size, or neuronal function. Moreover, while degradation of RAGA-1 in all somatic tissues alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, degradation of RAGA-1 in neurons only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.

Circulation: Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates (link)

Background: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs.

Methods: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in NOD-SCID mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated.

Results: We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion.

Conclusions: These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.

Stem cells / RegenMed

• Nature: Cholinergic neurons trigger epithelial Ca2+ currents to heal the gut (link)

• Diabetes Obes Metab: Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway (link)

• Cell Prolif: Promotion of diced cartilage survival and regeneration with grafting of small intestinal submucosa loaded with urine-derived stem cells (link)

• Curr Stem Cell Res Ther: Mesenchymal Stem Cell-Derived Exosomes Mitigate Acute Murine Liver Injury via Ets-1 and Heme Oxygenase-1 Up-regulation (link)

• Sci Transl Med: A bioengineered trachea-like structure improves survival in a rabbit tracheal defect model (link)

• NPJ Regen Med: Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration (link)

• Mol Neurobiol: Neuronal Stem Cells from Late-Onset Alzheimer Patients Show Altered Regulation of Sirtuin 1 Depending on Apolipoprotein E Indicating Disturbed Stem Cell Plasticity (link)

• Nature: A multi-stem cell basis for craniosynostosis and calvarial mineralization (link)

• Stem Cell Res Ther: Human umbilical cord-derived mesenchymal stem cells ameliorate perioperative neurocognitive disorder by inhibiting inflammatory responses and activating BDNF/TrkB/CREB signaling pathway in aged mice (link)

• Reviews:

  • Stem Cell Rev Rep: Recent Advances in CRISPR/Cas9 Delivery Approaches for Therapeutic Gene Editing of Stem Cells (link)

  • Stem Cells: Application of organoids in regenerative medicine (link)

  • Trends Mol Med: Bioelectronic medicine potentiates endogenous NSCs for neurodegenerative diseases (link)

Aging / Longevity

• Translational:

  • Zool Res: Evolution of p53 pathway-related genes provides insights into anticancer mechanisms of natural longevity in cetaceans (link)

  • Biosci Trends: A circadian rhythm-restricted diet regulates autophagy to improve cognitive function and prolong lifespan (link)

  • Proc Natl Acad Sci U S A: Neuronal MML-1/MXL-2 regulates systemic aging via glutamate transporter and cell nonautonomous autophagic and peroxidase activity (link)

  • EMBO Rep: The fruit fly acetyltransferase chameau promotes starvation resilience at the expense of longevity (link)

• Organ- and disease-specific:

  • Nat Nanotechnol: Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics (link)

  • J Cachexia Sarcopenia Muscle: Bisphosphonates attenuate age-related muscle decline in Caenorhabditis elegans (link)

  • Nat Aging: Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages (link)

  • JCI Insight: An aging-susceptible circadian rhythm controls cutaneous antiviral immunity (link)

• Other:

  • Geroscience: Blood biomarker profiles and exceptional longevity: comparison of centenarians and non-centenarians in a 35-year follow-up of the Swedish AMORIS cohort (link)

• Reviews:

  • Nat Aging: A framework for intestinal barrier dysfunction in aging (link)

  • Aging Cell: Senescent cells at the crossroads of aging, disease, and tissue homeostasis (link)

  • Biogerontology: Aging adipose tissue, insulin resistance, and type 2 diabetes (link)

Model systems / Protocols

• Models:

  • Adv Sci (Weinh): Cyclic Stretch Promotes Cellular Reprogramming Process through Cytoskeletal-Nuclear Mechano-Coupling and Epigenetic Modification (link)

  • Adv Sci (Weinh): Scalable Generation of Pre-Vascularized and Functional Human Beige Adipose Organoids (link)

  • Nat Methods: Spatiotemporal, optogenetic control of gene expression in organoids (link)

• Translational:

  • Nat Commun: Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors (link)

• Biomaterials:

  • Biofabrication: 3D-bioprintable endothelial cell-laden sacrificial ink for fabrication of microvessel networks (link)

  • Small: MiR-141-3p-Functionalized Exosomes Loaded in Dissolvable Microneedle Arrays for Hypertrophic Scar Treatment (link)

  • NPJ Regen Med: Immunomodulatory contribution of mast cells to the regenerative biomaterial microenvironment (link)

  • J Mater Chem B: Fabrication of 3D printed PCL/PEG artificial bile ducts as supportive scaffolds to promote regeneration of extrahepatic bile ducts in a canine biliary defect model (link)

  • Knee Surg Sports Traumatol Arthrosc: Fibronectin-coated polyurethane meniscal scaffolding supplemented with MSCs improves scaffold integration and proteoglycan production in a rabbit model (link)

  • Acta Biomater: Aligned Skeletal Muscle Assembly on a Biofunctionalized Plant Leaf Scaffold (link)

  • Biomacromolecules: Polysaccharide-Based Composite Hydrogel with Hierarchical Microstructure for Enhanced Vascularization and Skull Regeneration (link)

  • J Biomater Appl: Effect of adipose-derived stem cells seeding and surgical prefabrication on composite scaffold vascularization (link)

  • Biofabrication: Biomimetic human skin model patterned with rete ridges (link)

Clinical

• Pubs:

  • Stem Cell Res Ther: Intravitreal allogeneic mesenchymal stem cells: a non-randomized phase II clinical trial for acute non-arteritic optic neuropathy (link)

  • Stem Cell Res Ther: Evaluation of safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells in pediatric bronchiolitis obliterans syndrome (BoS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (link)

  • Angiology: Autologous Bone Marrow Stem Cells in Patients With Critical Limb Ischaemia not Eligible for Revascularization: A Single Centre Experience (link)

  • Knee Surg Sports Traumatol Arthrosc: Mesenchymal stem cell implantation provides short-term clinical improvement and satisfactory cartilage restoration in patients with knee osteoarthritis but the evidence is limited: a systematic review performed by the early-osteoarthritis group of ESSKA-European knee associates section (link)

• Corporate:

  • United Therapeutics: United Therapeutics Announces Recent Milestones for its Heart and Kidney Xenotransplantation Programs (link)

  • FDA: Platform designations: FDA's new cell and gene therapy super office director sees potential (link)

  • FDA: Scientific Challenges and Opportunities to Advance the Development of Individualized Cellular and Gene Therapies (link)

• Newly posted studies:

  • NCT06041620: Safety and Efficacy Evaluation of Autologous CRISPR-Cas12b Edited Hematopoietic Stem Cells (link)

Other (Articles, Perspectives, etc.)

• EMBO Rep: Striking the right balance between youth and experience (link)

• Business:

  • JURA Bio: A new George Church startup raises $16M. The first-time founders have a ‘crazy vision’ to bring ML to cell therapy (link)

  • Coya Therapeutics: Coya Therapeutics Licenses Exclusive Worldwide rights to Exosome Engineering Technology (EET) from Carnegie Mellon University (CMU) (link)

  • Seraxis: Seraxis Announces Closing of Second VC Tranche and Successful Completion of Preclinical Studies of Pancreatic Organoids From Seraxis’ Novel Pancreas-Derived Stem Cells (link)

  • Nat Biotechnol: Pharma deal making: a bright spot amid the gloom (link)

  • WSJ: Synthetic Biology Moves From the Lab to the Marketplace (link)

• Other interesting papers:

  • Nat Rev Drug Discov: Drug delivery systems for CRISPR-based genome editors (link)

  • Science: Predicting pathogenic protein variants (link)

  • JAMA Psychiatry:Network-Based Spreading of Gray Matter Changes Across Different Stages of Psychosis (link)

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Trial and landscape background

TERN-501 is being investigated in the DUET study (NCT05415722), a 162-patient, 7-arm, Phase 2a testing TERN-501 +/- TERN-101 (an FXR agonist) against placebo in biopsy- or image-confirmed NASH patients. The study completed enrollment in February 2023 and the longest endpoint tested is 16 weeks, meaning all patients should have completed the trial and the company may already be under data lock. …

Prospects for the upcoming topline data

In short, we do not believe the topline DUET data will be competitive, for the following reasons:

Limited single agent activity. The topline results for both the TERN-501 Phase 1 (here) and TERN-101 Phase 2a LIFT study (here) were not notably competitive on any metric, and were notably worse in LDL. In MRI-PDFF measures, TERN-101 showed statistical significance vs PBO at Week 6 but not Week 12; Week 12 is the endpoint for DUET. We would need to see PBO adjusted MRI-PDFF reductions >25% to be confident in further trials.

Limited confidence in dual-agent activity. Ascletis has presented healthy volunteer data of its fixed-dose THR-β/FXR dual agonist ASC43F (here). In the combo, the FXR agonist active portion showed decreased Cmax, t1/2, and AUC vs monotherapy (the active THR-β agonist showed increases in HVs, but decreases in beagles), indicating potential for negative crosstalk between the pathways. Terns showed strong preclinical combination data at EASL this year (here) and disclosed in a patent (here), but clinical combinations of FXRs with multiple modalities have produced negative or non-competitive results (+ACC; +GLP-1; +CCR2/5).

cT1 data only marginally useful. cT1 is being measured as a secondary endpoint in DUET. TERN-101 was statistically significant vs PBO on cT1 decrease, a novel MRI measure “for assessing a composite of liver inflammation and fibrosis” (source). It can be used for recruiting NASH vs NAFL patients and is correlated to NAFL severity. This endpoint is likely to be hit in DUET (i.e., stat sig vs PBO), but given that every 81ms decrease in cT1 is associated with a 12% relative decline in PDFF (source), extrapolating the Phase 2a dose data would mean only ~8.5% decrease in PDFF, or 3x lower than the lowest competitive bound. Additionally, PDFF and cT1 are only weakly correlated (source) as seen in the LIFT study.

TERN-101 could negatively impact safety and biomarkers. While TERN-101 is a significantly safer FXR agonist vs first gen assets like obetacholic acid (NASH Phase 3 data here), 11.5-17.4% of patients still reported pruritus (vs 0% of PBO), and there were significant increases in LDL and decreases in HDL even at the lowest doses. (Previous trials have shown statins can improve this profile.) TERN-501 has looked very tolerable but the combination may make this a “dirty” THR-β, undercutting its prior success. As discussed above, TERN-501 mono is unlikely to be competitive, meaning -501 + -101 must be both safe and superior in efficacy.

Conclusion

Investors were unimpressed with the LIFT data release in 2019, driving the stock down 48% in a month (vs flat for VKTX and +5% for the XBI). … We see a repeat of this unfortunate situation as the company hits the endpoints but is not in a competitive position to fund late-stage trials totaling a couple hundred million.

/ - / - / - / - / - / - / - / - /

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

J Neuroimmune Pharmacol: SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer's Disease (link)

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer's disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1β, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.

Adv Sci (Weinh): Precise Correction of Lhcgr Mutation in Stem Leydig Cells by Prime Editing Rescues Hereditary Primary Hypogonadism in Mice (link)

Hereditary primary hypogonadism (HPH), caused by gene mutation related to testosterone synthesis in Leydig cells, usually impairs male sexual development and spermatogenesis. Genetically corrected stem Leydig cells (SLCs) transplantation may provide a new approach for treating HPH. Here, a novel nonsense-point-mutation mouse model (LhcgrW495X ) is first generated based on a gene mutation relative to HPH patients. To verify the efficacy and feasibility of SLCs transplantation in treating HPH, wild-type SLCs are transplanted into LhcgrW495X mice, in which SLCs obviously rescue HPH phenotypes. Through comparing several editing strategies, optimized PE2 protein (PEmax) system is identified as an efficient and precise approach to correct the pathogenic point mutation in Lhcgr. Furthermore, delivering intein-split PEmax system via lentivirus successfully corrects the mutation in SLCs from LhcgrW495X mice ex vivo. Gene-corrected SLCs from LhcgrW495X mice exert ability to differentiate into functional Leydig cells in vitro. Notably, the transplantation of gene-corrected SLCs effectively regenerates Leydig cells, recovers testosterone production, restarts sexual development, rescues spermatogenesis, and produces fertile offspring in LhcgrW495X mice. Altogether, these results suggest that PE-based gene editing in SLCs ex vivo is a promising strategy for HPH therapy and is potentially leveraged to address more hereditary diseases in reproductive system.

Nat Metab: Dynamic lipidome alterations associated with human health, disease and ageing (link)

Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.

Nature: A vertebral skeletal stem cell lineage driving metastasis (link)

Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases1-4. The basis for this distinct biology of vertebral bone has so far remained unknown. Here we identify a vertebral skeletal stem cell (vSSC) that co-expresses ZIC1 and PAX1 together with additional cell surface markers. vSSCs display formal evidence of stemness, including self-renewal, label retention and sitting at the apex of their differentiation hierarchy. vSSCs are physiologic mediators of vertebral bone formation, as genetic blockade of the ability of vSSCs to generate osteoblasts results in defects in the vertebral neural arch and body. Human counterparts of vSSCs can be identified in vertebral endplate specimens and display a conserved differentiation hierarchy and stemness features. Multiple lines of evidence indicate that vSSCs contribute to the high rates of vertebral metastatic tropism observed in breast cancer, owing in part to increased secretion of the novel metastatic trophic factor MFGE8. Together, our results indicate that vSSCs are distinct from other skeletal stem cells and mediate the unique physiology and pathology of vertebrae, including contributing to the high rate of vertebral metastasis.

Stem cells / RegenMed

• CNS Neurosci Ther: Human umbilical cord mesenchymal stem cell-derived exosomes attenuate neuroinflammation and oxidative stress through the NRF2/NF-κB/NLRP3 pathway (link)

• Brain Res Bull: Umbilical cord mesenchymal stem cell-conditioned medium inhibits microglial activation to ameliorate neuroinflammation in amyotrophic lateral sclerosis mice and cell models (link)

• ACS Nano: Targeted Delivery of RGD-CD146+CD271+ Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Promotes Blood-Spinal Cord Barrier Repair after Spinal Cord Injury (link)

• Elife: Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy (link)

• Sci Rep: Umbilical cord mesenchymal stem cells relieve osteoarthritis in rats through immunoregulation and inhibition of chondrocyte apoptosis (link)

• Stem Cell Res Ther: Biodistribution of mesenchymal stromal cell-derived extracellular vesicles administered during acute lung injury (link)

• Skelet Muscle: Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of the skeletal muscle (link)

• Stem Cell Res Ther: Injury-experienced satellite cells retain long-term enhanced regenerative capacity (link)

• Reviews:

  • Endocrinology: Progress Toward and Challenges Remaining for Thyroid Tissue Regeneration (link)

  • Stem Cell Rev Rep: Cell-based Therapies for Corneal and Retinal Disorders (link)

  • J Physiol: Astrocytes in functional recovery following central nervous system injuries (link)

  • Stem Cell Reports: A Perspective, Editorial, and SnapShot on ISSCR standards

Aging / Longevity

• Translational:

  • Rejuvenation Res: Endocrine and epigenetic regulation as common pathways underlying the genetic basis of sleep traits and longevity (link)

  • Geroscience: Geroprotective interventions converge on gene expression programs of reduced inflammation and restored fatty acid metabolism (link)

  • J Gerontol A Biol Sci Med Sci: Fluoxetine promotes longevity via reactive oxygen species in Caenorhabditis elegans (link)

  • PLoS Biol: A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans (link)

• Organ- and disease-specific:

  • Aging Cell: Transcriptional changes of the aging lung (link)

  • Epigenomics: Associations between GrimAge acceleration and pulmonary function in the Coronary Artery Risk Development in Young Adults (CARDIA) study (link)

  • Rejuvenation Res: Intense caloric restriction from birth prevents cardiovascular aging in rats (link)

  • Brain Behav Immun: Sex differences in microglia function in aged rats underlie vulnerability to cognitive decline (link)

  • Nat Aging: Transcriptional and epigenetic decoding of the microglial aging process (link)

  • J Gerontol A Biol Sci Med Sci: Epigenetic aging and rheumatoid arthritis (link)

  • Dev Cell: Mitochondrial GTP metabolism controls reproductive aging in C. elegans (link)

• Other:

  • Sci Rep: Diagnostic accuracy of brain age prediction in a memory clinic population and comparison with clinically available volumetric measures (link)

  • Aging (Albany NY): Fail-tests of DNA methylation clocks, and development of a noise barometer for measuring epigenetic pressure of aging and disease (link)

  • Biogerontology: Plasma proteins as potential biomarkers of aging of single tissue and cell type (link)

• Reviews:

  • Ageing Res Rev: Hormesis Defines The Limits Of Lifespan (link)

  • Semin Immunol: Proteostasis in T cell aging (link)

Model systems / Protocols

• Models:

  • Sci Rep: An inspired microenvironment of cell replicas to induce stem cells into keratocyte-like dendritic cells for corneal regeneration (link)

  • Sci Rep: Truncated vitronectin with E-cadherin enables the xeno-free derivation of human embryonic stem cells (link)

  • Biofabrication: Biofabrication of an in-vitro bone model for Gaucher disease (link)

• Translational:

  • Xenotransplantation: Modeling human anti-pig xenoimmune responses in a pig artery tissue grafted humanized mouse model (link)

  • Cell Mol Neurobiol: A Perfused In Vitro Human iPSC-Derived Blood-Brain Barrier Faithfully Mimics Transferrin Receptor-Mediated Transcytosis of Therapeutic Antibodies (link)

  • Nature: Single-cell brain organoid screening identifies developmental defects in autism (link)

• Biomaterials:

  • ACS Appl Mater Interfaces: Engineering Highly Vascularized Bone Tissues by 3D Bioprinting of Granular Prevascularized Spheroids (link)

  • Adv Healthc Mater: Glycoprotein Injectable Hydrogels Promote Accelerated Bone Regeneration Through Angiogenesis and Innervation (link)

  • Tissue Eng Regen Med: Reactive Oxygen Species Scavenging Hydrogel Regulates Stem Cell Behavior and Promotes Bone Healing in Osteoporosis (link)

  • Biomed Mater: Development and optimisation of hydroxyapatite-polyethylene glycol diacrylate hydrogel inks for 3D printing of bone tissue engineered scaffolds (link)

  • Adv Mater: Hydrogen Ion Capturing Hydrogel Microspheres for Reversing Inflammaging (link)

  • ACS Nano: In Vivo Photoacoustic Monitoring of Stem Cell Location and Apoptosis with Caspase-3-Responsive Nanosensors (link)

  • ACS Nano: Robust and Multifunctional Nanoparticles Assembled from Natural Polyphenols and Metformin for Efficient Spinal Cord Regeneration (link)

Clinical

• Pubs:

  • Stem Cell Res Ther: Suprachoroidal spheroidal mesenchymal stem cell implantation in retinitis pigmentosa: clinical results of 6 months follow-up (link)

  • Orthop J Sports Med: Safety and Efficacy of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Patellar Tendinopathy (With Gap >3 mm) in Patients: 12-Month Follow-up Results of a Phase 1/2 Clinical Trial (link)

  • Stem Cell Rev Rep: Safety and Efficacy of DT-DEC01 Therapy in Duchenne Muscular Dystrophy Patients: A 12 - Month Follow-Up Study After Systemic Intraosseous Administration (link)

  • Minerva Endocrinol (Torino): Regenerative treatment with platelet-rich plasma in patients with refractory erectile dysfunction: short-term outcomes and predictive value of mean platelet volume (link)

  • Curr Stem Cell Res Ther: Comparative efficacy of endogenous stem cells recruiting hydrogels and stem cell-loaded hydrogels in knee cartilage regeneration: a meta-analysis (link)

  • Stem Cell Res Ther: What is the optimal dose of adipose-derived mesenchymal stem cells treatment for knee osteoarthritis? A conventional and network meta-analysis of randomized controlled trials (link)

• Corporate:

  • Sana Biotech: The Company expects to file an investigational new drug application for its SC291 product candidate in autoimmune diseases in the fourth quarter of 2023 (link)

• Newly posted studies:

  • NCT06030648: MT2022-01: MSCs for ALD (link)

Other (Articles, Perspectives, etc.)

• Nat Biotechnol: Targeting hematopoietic stem cells in vivo (link)

• Business:

  • Nat Biotechnol: Public biotech in 2022 - the numbers (link)

• Other interesting papers:

  • Lancet Reg Health West Pac: Caffeine intake interacts with Asian gene variants in Parkinson's disease: a study in 4488 subjects (link)

  • Nat Biomed Eng: Suppression of cytokine release syndrome during CAR-T-cell therapy via a subcutaneously injected interleukin-6-adsorbing hydrogel (link)

  • Nature: C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation (link)

  • Lancet Diabetes Endocrinol: Life expectancy associated with different ages at diagnosis of type 2 diabetes in high-income countries: 23 million person-years of observation (link)

One part I did not fully appreciate was the affect on caregivers. Clinical scales such as the CRS and BAS seek to capture caregiver burden in these and other disorders, and companies often tout improvements in these metrics as ‘key secondary endpoints’. But caregiver stress extends far beyond pediatric epileptic disorders, and I wanted to capture that this week with some recent papers (below) that highlight the often unsung heroes (and sufferers) around a given illness.

• Wishing for an end? Longitudinal analysis of suicidal ideation among informal caregivers inside and outside their household in different welfare systems of Europe (source)

  • “Transitioning into caregiving inside the household was associated with higher odds of suicidal ideation, in particular if they transitioned into care for partners or parents...”

• Associations between klotho and telomere biology in high stress caregivers (source)

  • “Our results suggest that klotho levels and telomere length may be associated through a coordinated downregulation of longevity factors occurring under higher stress caregiving conditions.”

• Prevalence of depression among caregivers based on the condition and relationship of care recipient (source)

  • “We found that caregivers who were female, American Indian/Alaskan Native, race-not-listed, earning less than $15,000 a year, or did not complete high school, had higher rates of depression diagnosis. The rates of depression were higher among caregivers if the recipient had a mental or chronic respiratory condition, or if the recipient was their live-in partner.”

• Long-term parental distress after pediatric hematopoietic stem cell transplantation for nonmalignant diseases (source)

  • “Fathers of HSCT recipients…reported higher overall distress levels and had more emotional distress compared to fathers of healthy children.”

• PTSD Symptoms Among Family Members of Patients With ARDS Caused by COVID-19 After 12 Months (source)

  • “Acute respiratory distress syndrome (ARDS) caused by COVID-19, compared with other causes of ARDS, was significantly associated with a higher prevalence of symptoms of posttraumatic stress disorder (PTSD), anxiety, and depression in family members 3 months after patient discharge or death.”

Fortunately there are support groups sponsored by patient advocacy organizations, and new strategies seek to involve caregivers in the treatment process of care recipients (see: Who cares for the carer?). Still, these individuals deserve more than they are currently receiving.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Aging Cell: Loss of Pla2r1 decreases cellular senescence and age-related alterations caused by aging and Western diets (link)

Cellular senescence is induced by many stresses including telomere shortening, DNA damage, oxidative, or metabolic stresses. Senescent cells are stably cell cycle arrested and they secrete many factors including cytokines and chemokines. Accumulation of senescent cells promotes many age-related alterations and diseases. In this study, we investigated the role of the pro-senescent phospholipase A2 receptor 1 (PLA2R1) in regulating some age-related alterations in old mice and in mice subjected to a Western diet, whereas aged wild-type mice displayed a decreased ability to regulate their glycemia during glucose and insulin tolerance tests, aged Pla2r1 knockout (KO) mice efficiently regulated their glycemia and displayed fewer signs of aging. Loss of Pla2r1 was also found protective against the deleterious effects of a Western diet. Moreover, these Pla2r1 KO mice were partially protected from diet-induced senescent cell accumulation, steatosis, and fibrosis. Together these results support that Pla2r1 drives several age-related alterations, especially in the liver, arising during aging or through a Western diet.

Nucleic Acids Res: Open Genes-a new comprehensive database of human genes associated with aging and longevity (link)

The Open Genes database was created to enhance and simplify the search for potential aging therapy targets. We collected data on 2402 genes associated with aging and developed convenient tools for searching and comparing gene features. A comprehensive description of genes has been provided, including lifespan-extending interventions, age-related changes, longevity associations, gene evolution, associations with diseases and hallmarks of aging, and functions of gene products. For each experiment, we presented the necessary structured data for evaluating the experiment's quality and interpreting the study's findings. Our goal was to stay objective and precise while connecting a particular gene to human aging. We distinguished six types of studies and 12 criteria for adding genes to our database. Genes were classified according to the confidence level of the link between the gene and aging. All the data collected in a database are provided both by an API and a user interface. The database is publicly available on a website at https://open-genes.org/.

Adv Mater: Pericardial Delivery of SDF-1α-encapsulated Puerarin Hydrogel Promotes Endogenous Repair and Electrical Coupling After Myocardial Infarction (link)

The SDF-1α/CXCR4 axis contributes to myocardial protection after MI by recruiting endogenous stem cells into the ischemic tissue. However, excessive inflammatory macrophages are also recruited simultaneously, aggravating myocardial damage. More seriously, the increased inflammation contributes to abnormal cardiomyocyte electrical coupling, leading to inhomogeneities in ventricular conduction and retarded conduction velocity. It is highly desirable to selectively recruit the stem cells but block the inflammation. In this work, the SDF-1α-encapsulated Puerarin (PUE) hydrogel (SDF-1α@PUE) that is capable of enhancing endogenous stem cell homing and simultaneously polarizing the recruited monocyte/macrophages into a repairing phenotype. Flow cytometry analysis of the treated heart tissue shows that endogenous bone marrow mesenchymal stem cells (BMSCs), hemopoietic stem cells (HSCs), and immune cells are recruited while SDF-1α@PUE efficiently polarized the recruited monocytes/macrophages into the M2 type. These macrophages influence the preservation of Cx43 expression which modulates intercellular coupling and improves electrical conduction. Furthermore, by taking advantage of the improved "soil", the recruited stem cells mediates an improved cardiac function by preventing deterioration, promoting neovascular architecture, and reducing infarct size. Our findings demonstrate a promising therapeutic platform for MI that not only facilitates heart regeneration but also reduces the risk of cardiac arrhythmias.

J Control Release: Gene-activated hyaluronic acid-based cryogels for cartilage tissue engineering (link)

Articular cartilage injuries are very frequent lesions that if left untreated may degenerate into osteoarthritis. Gene transfer to mesenchymal stem cells (MSCs) provides a powerful approach to treat these lesions by promoting their chondrogenic differentiation into the appropriate cartilage phenotype. Non-viral vectors constitute the safest gene transfer tools, as they avoid important concerns of viral systems including immunogenicity and insertional mutagenesis. However, non-viral gene transfer usually led to lower transfection efficiencies when compared with their viral counterparts. Biomaterial-guided gene delivery has emerged as a promising alternative to increase non-viral gene transfer efficiency by achieving sustained delivery of the candidate gene into cellular microenvironment. In the present study, we designed hyaluronic acid-based gene-activated cryogels (HACGs) encapsulating a novel formulation of non-viral vectors based on niosomes (P80PX) to promote MSCs in situ transfection. The developed HACG P80PX systems showed suitable physicochemical properties to promote MSCs in situ transfection with very low cytotoxicity. Incorporation of a plasmid encoding for the transcription factor SOX9 (psox9) into HACG P80PX systems led to an effective MSCs chondrogenic differentiation with reduced expression of fibrocartilage and hypertrophic markers. The capacity of the developed systems to restore cartilage extracellular matrix was further confirmed in an ex vivo model of chondral defect.

Stem cells / RegenMed

• Nat Commun: A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury (link)

• FASEB J: Disruption of the primocolonizing microbiota alters epithelial homeostasis and imprints stem cells in the colon of neonatal piglets (link)

• Stem Cell Res Ther: Transplanted ENSCs form functional connections with intestinal smooth muscle and restore colonic motility in nNOS-deficient mice (link)

• Glia: Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis (link)

• Glia: Human iPSC-derived endothelial cells promote CNS remyelination via BDNF and mTORC1 pathway (link)

• Stem Cell Res Ther: Local transplantation of mesenchymal stem cells improves encephalo-myo-synangiosis-mediated collateral neovascularization in chronic brain ischemia (link)

• Mol Med: Hypoxia-treated adipose mesenchymal stem cell-derived exosomes attenuate lumbar facet joint osteoarthritis (link)

• Stem Cell Res Ther: Low-glucose culture environment can enhance the wound healing capability of diabetic adipose-derived stem cells (link)

• JCI Insight: Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury (link)

• Reviews:

  • Nat Rev Rheumatol: Therapeutic potential in rheumatic diseases of extracellular vesicles derived from mesenchymal stromal cells (link)

  • Regen Med: From fetal tendon regeneration to adult therapeutic modalities: TGF-β3 in scarless healing (link)

  • Stem Cell Res Ther: Enhancing mesenchymal stem cell survival and homing capability to improve cell engraftment efficacy for liver diseases (link)

Aging / Longevity

• Translational:

  • Aging Cell: Distinct physiological characteristics and altered glucagon signaling in GHRH knockout mice: Implications for longevity (link)

• Organ- and disease-specific:

  • Cell Metab: Deciphering the decline of metabolic elasticity in aging and obesity (link)

  • Hum Reprod: Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction (link)

  • Cell Rep: Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan (link)

• Other:

  • Proc Natl Acad Sci U S A: A step toward precision gerontology: Lifespan effects of calorie and protein restriction are consistent with predicted impacts on entropy generation (link)

  • Lancet Healthy Longev: Healthy ageing from birth to age 84 years in the Helsinki Birth Cohort Study, Finland: a longitudinal study (link)

• Reviews:

  • Lancet Healthy Longev: Correspondences / editorials on sleep, physical activity + sleep, and cohort studies in aging

  • Epigenomics: Pathological epigenetic events and reversibility review: the intersection between hallmarks of aging and developmental origin of health and disease (link)

  • Br J Clin Pharmacol: Optimising preclinical models of aging for translation to clinical trials (link)

Model systems / Protocols

• Models:

  • Cell Mol Life Sci: Human myofibroblasts increase the arrhythmogenic potential of human induced pluripotent stem cell-derived cardiomyocytes (link)

  • Nature: Complete human day 14 post-implantation embryo models from naïve ES cells (link)

  • Nat Methods: Setting standards for stem cells (link)

• Translational:

  • Cell Discov: Derivation of transgene-free bat induced pluripotent stem cells amenable to chimera formation in mice, pigs, and chicks (link)

  • J Infect Dis: Report of the Assay Guidance Workshop on 3-Dimensional Tissue Models for Antiviral Drug Development (link)

  • Cardiovasc Res: Atrial fibrillation-associated electrical remodelling in human induced pluripotent stem cell-derived atrial cardiomyocytes: a novel pathway for antiarrhythmic therapy development (link)

• Biomaterials:

  • Biomater Sci: Sericin nano-gel agglomerates mimicking the pericellular matrix induce the condensation of mesenchymal stem cells and trigger cartilage micro-tissue formation without exogenous stimulation of growth factors in vitro (link)

  • Biotechnol Bioeng: Macrophage cell morphology-imprinted substrates can modulate mesenchymal stem cell behaviors and macrophage M1/M2 polarization for wound healing applications (link)

  • Adv Mater: Mechano-activated Cell Therapy for Accelerated Diabetic Wound Healing (link)

  • Biomater Adv: 3D-printed LEGO®-inspired titanium scaffolds for patient-specific regenerative medicine (link)

Clinical

• Pubs:

  • Nat Med: Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (link)

  • J Clin Endocrinol Metab: Thyroid hormone levels correlate with the maturation of implanted pancreatic endoderm cells in patients with type 1 diabetes (link)

  • Knee Surg Sports Traumatol Arthrosc: Midterm results of intra-articular stromal vascular fraction injection for the treatment of knee osteoarthritis (link)

• Corporate:

  • BioCardia: BioCardia Announces Interim Efficacy Results in Phase III Pivotal CardiAMP Cell Therapy Heart Failure Trial (link)

  • Beam Tx: Beam Therapeutics Announces First Patient Dosed in Phase 1/2 Trial of BEAM-201 in Relapsed, Refractory T-ALL/T-LL (link)

• Newly posted studies:

  • NCT06024226: Role of MDSCs and Cancer Stem Cells and Their Cross Talks in NSCLC (MyéloLungSC) (link)

  • NCT06024876: A Clinical Study Evaluating the Safety and Efficacy of CS-101 in Treating Subjects With β-thalassemia (link)

  • NCT06028763: Comparative Study of Heparin-Conjugated Gel vs. Microfracture for Surgical Treatment of Ankle Joint Cartilage Lesions (link)

  • NCT06026995: Clinical Study on PEG-rhG-CSF in Mobilizing Autologous Hematopoietic Stem Cells (link)

Other (Articles, Perspectives, etc.)

• JAMA Netw Open: Procurement of Pancreatic Tissue for Research From Deceased Donors Before vs After the CMS Final Rule in 2020 (link)

• Business:

  • Endpoints: Exclusive: Khosla Ventures leads seed round in mRNA biotech looking to reverse aging by lengthening telomeres (link)

  • Endpoints: iPSC biotech Shoreline Biosciences wins patent infringement suit over Fate, Whitehead Institute (link)

  • Nat Rev Drug Discov: Upcoming market catalysts in Q4 2023 (link)

• Other interesting papers:

  • Proc Natl Acad Sci U S A:Nasal administration of anti-CD3 monoclonal antibody ameliorates disease in a mouse model of Alzheimer's disease (link)

iPSCs:

• Fibroblasts / keratinocytes: Original source of cells for dedifferentiation to iPSCs. Easily acquired via skin biopsy, but require in vitro expansion before transformation to ensure adequate pluripotent cells.

• Peripheral blood mononuclear cells (PBMCs): Acquired via blood draw. Common cell used for many procedures so isolation is established, and cell volumes are adequate for immediate transformation. Challenges come from general handling of blood, such as infection and storage risks.

MSCs:

• Bone marrow: Extremely well established in the literature including PMDA-approved products, though extraction is painful and challenging. Still no strong conensus on which diseases are most ideal for treatment, and new evidence points to pretreatment of BMSCs as important for efficacy.

• Placenta: Ideal for allogeneic transplants due to immune modulatory properties and poor immunogenecity, and cells from different regions (such as placenta vs amniotic sac) and sources (maternal vs fetal) may have distinct properties. Can be banked for use in the future.

• Blood (including menstrual): Peripheral blood MSCs are isolated similarly to PBMCs described above, and show the ability to differentiate to adipocytes and osteoblasts. Menstrual blood-derived stem cells (MenSCs) and endometrial MSCs were originally identified as biomarkers and targets for endometriosis treatment, but have since expanded to all areas of MSC research due to the ectopic nature of endometriosis.

• Urine: Small number of secreted cells in the urine can contain MSC phenotypes and be differentiated to iPSCs. Advantage in non-invasive collection, but yield is likely extremely low (I have not found a good protocol on cell expansion, but I guess you could just keep collecting from the same patient over 24hrs? I see a high risk for contamination there though.).

• Dental pulp: Vascularized layer below the enamel and dentin. Dental pulp stem cells are being investigated for orthopedic and oral maxillofacial reconstruction due to preference for osteogenic differentiation. Not a mature technology.

• Antlers: From the paper: “Antlers are the only fully regenerable mammalian appendages whose annual renewal is initiated by antler stem cells (ASCs), defined as a specialized type of mesenchymal stem cells (MSCs) with embryonic stem cell properties.” Seems farfetched - only 122 papers in PubMed since the first in 2003.

• iPSCs: Direct differentiation of iPSCs to MSCs.

HSCs:

• Cord blood: Collected from the post-partum placenta and cord blood. More primitive than bone marrow or peripheral blood, and therefore easier to manipulate to different hematopoietic cell lines with cytokines. Alternative to bone marrow transplantation with many FDA-approved therapies.

• Bone marrow (adult): Natural source for HSCs, but HSC niche has been difficult to define and is complicated by heterogenous stem and progenitor cell populations. Can be effectively targeted by gene therapies for systemic improvements (i.e., sickle cell anemia).

• iPSCs: Direct differentiation of iPSCs to HSCs.

A future post will dive in to some of the better known progenitor cells, such as different hematopoeitc lineages or neural progenitors, which are becoming hot topics for drug discovery due to their ability to influence multiple cell and organ types.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

PLoS Biol: Dietary change without caloric restriction maintains a youthful profile in ageing yeast (link)

Caloric restriction increases lifespan and improves ageing health, but it is unknown whether these outcomes can be separated or achieved through less severe interventions. Here, we show that an unrestricted galactose diet in early life minimises change during replicative ageing in budding yeast, irrespective of diet later in life. Average mother cell division rate is comparable between glucose and galactose diets, and lifespan is shorter on galactose, but markers of senescence and the progressive dysregulation of gene expression observed on glucose are minimal on galactose, showing that these are not intrinsic aspects of replicative ageing but rather associated processes. Respiration on galactose is critical for minimising hallmarks of ageing, and forced respiration during ageing on glucose by overexpression of the mitochondrial biogenesis factor Hap4 also has the same effect though only in a fraction of cells. This fraction maintains Hap4 activity to advanced age with low senescence and a youthful gene expression profile, whereas other cells in the same population lose Hap4 activity, undergo dramatic dysregulation of gene expression and accumulate fragments of chromosome XII (ChrXIIr), which are tightly associated with senescence. Our findings support the existence of two separable ageing trajectories in yeast. We propose that a complete shift to the healthy ageing mode can be achieved in wild-type cells through dietary change in early life without caloric restriction.

Nat Aging: Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems (link)

Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias)1,2. These processes are accompanied by an aberrant accumulation of mitochondria in HSCs3. The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.

Adv Mater: Direct 3D-Bioprinting of hiPSC-derived Cardiomyocytes to Generate Functional Cardiac Tissues (link)

3D-bioprinting is a promising technology to produce human tissues as drug screening tool or for organ repair. However, direct printing of living cells has proven difficult. Here, we present a method to directly 3D-bioprint human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes embedded in a collagen-hyaluronic acid ink generating centimeter-sized functional ring- and ventricle-shaped cardiac tissues in an accurate and reproducible manner. The printed tissues contained hiPSC-derived cardiomyocytes with well-organized sarcomeres and exhibited spontaneous and regular contractions, which persisted for several months and were able to contract against passive resistance. Importantly, beating frequencies of the printed cardiac tissues could be modulated by pharmacological stimulation. This approach opens up new possibilities for generating complex functional cardiac tissues as models for advanced drug screening or as tissue grafts for organ repair or replacement.

ACS Appl Mater Interfaces: Multifunctional Silk Fibroin/Carbon Nanofiber Scaffolds for In Vitro Cardiomyogenic Differentiation of Induced Pluripotent Stem Cells and Energy Harvesting from Simulated Cardiac Motion (link)

In this proof-of-concept study, cardiomyogenic differentiation of induced pluripotent stem cells (iPSCs) is combined with energy harvesting from simulated cardiac motion in vitro. To achieve this, silk fibroin (SF)-based porous scaffolds are designed to mimic the mechanical and physical properties of cardiac tissue and used as triboelectric nanogenerator (TENG) electrodes. The load-carrying mechanism, β-sheet content, degradation characteristics, and iPSC interactions of the scaffolds are observed to be interrelated and regulated by their pore architecture. The SF scaffolds with a pore size of 379 ± 34 μm, a porosity of 79 ± 1%, and a pore interconnectivity of 67 ± 1% upregulated the expression of cardiac-specific gene markers TNNT2 and NKX2.5 from iPSCs. Incorporating carbon nanofibers (CNFs) enhances the elastic modulus of the scaffolds to 45 ± 3 kPa and results in an electrical conductivity of 0.021 ± 0.006 S/cm. The SF and SF/CNF scaffolds are used as conjugate TENG electrodes and generate a maximum power output of 0.37 × 10-3 mW/m2, with an open-circuit voltage and a short circuit current of 0.46 V and 4.5 nA, respectively, under simulated cardiac motion. A novel approach is demonstrated for fabricating scaffold-based cardiac patches that can serve as tissue scaffolds and simultaneously allow energy harvesting.

Stem cells / RegenMed

• ACS Appl Mater Interfaces: In Situ Cross-Linkable Hyaluronic-Ferulic Acid Conjugate Containing Bucladesine Nanoparticles Promotes Neural Regeneration after Spinal Cord Injury (link)

• CNS Neurosci Ther: Hypoxic-preconditioned mesenchymal stem cell-derived small extracellular vesicles promote the recovery of spinal cord injury by affecting the phenotype of astrocytes through the miR-21/JAK2/STAT3 pathway (link)

• J Mater Sci Mater Med: Enhanced therapeutic effects of mesenchymal stem cell-derived extracellular vesicles within chitosan hydrogel in the treatment of diabetic foot ulcers (link)

• Stem Cells Transl Med: External Application of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Hyaluronic Acid Gel Repairs Foot Wounds of Types I and II Diabetic Rats Through Paracrine Action Mode (link)

• ESC Heart Fail: Vagus nerve stimulation-induced stromal cell-derived factor-l alpha participates in angiogenesis and repair of infarcted hearts (link)

• J Nanobiotechnology: Nanoparticles systemically biodistribute to regenerating skeletal muscle in DMD (link)

• Sci Adv: Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells (link)

• Curr Stem Cell Res Ther: Interferon-gamma treatment of human umbilical cord mesenchymal stem cells can significantly reduce damage associated with diabetic peripheral neuropathy in mice (link)

• Biomater Res: Self-organized insulin-producing β-cells differentiated from human omentum-derived stem cells and their in vivo therapeutic potential (link)

• Reviews:

  • Tissue Eng Regen Med: Biotherapeutic Applications of Platelet-Rich Plasma in Regenerative Medicine (link)

  • Tissue Eng Regen Med: Using Pre-Clinical Studies to Explore the Potential Clinical Uses of Exosomes Secreted from Induced Pluripotent Stem Cell-Derived Mesenchymal Stem cells (link)

  • Eur Heart J: The ESC Working Group on cardiovascular regenerative and reparative medicine (link)

Aging / Longevity

• Translational:

  • Geroscience: Proteomic changes induced by longevity-promoting interventions in mice (link)

  • Nat Commun: Downregulation of transposable elements extends lifespan in Caenorhabditis elegans (link)

  • Cell Mol Life Sci: Chaotic aging: intrinsically disordered proteins in aging-related processes (link)

  • Cell Mol Immunol: Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment (link)

• Organ- and disease-specific:

  • Sci Transl Med: Farnesol prevents aging-related muscle weakness in mice through enhanced farnesylation of Parkin-interacting substrate (link)

  • Sci Rep: Single-cell RNA sequencing to detect age-associated genes that identify senescent cells in the liver of aged mice (link)

  • Nat Aging: Age-associated decline in RAB-10 efficacy impairs intestinal barrier integrity (link)

  • Proc Natl Acad Sci U S A: Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α (link)

  • Aging (Albany NY): Reorganization of pancreas circadian transcriptome with aging (link)

  • Biogerontology: Aging impairs recovery from stress-induced depression in male rats possibly by alteration of microRNA-101 expression and Rac1/RhoA pathway in the prefrontal cortex (link)

• Other:

  • Geroscience: Metabolic biomarkers using nuclear magnetic resonance metabolomics assay for the prediction of aging-related disease risk and mortality: a prospective, longitudinal, observational, cohort study based on the UK Biobank (link)

  • Aging Cell: Fingerstick blood assay maps real-world NAD+ disparity across gender and age (link)

• Reviews:

  • Ageing Res Rev: Biomarkers of aging in frailty and age-associated disorders: state of the art and future perspective (link)

Model systems / Protocols

• Models:

  • Exp Mol Med: Scalable production of tissue-like vascularized liver organoids from human PSCs (link)

  • Stem Cell Rev Rep: Using Ribonucleoprotein-based CRISPR/Cas9 to Edit Single Nucleotide on Human Induced Pluripotent Stem Cells to Model Type 3 Long QT Syndrome (SCN5A±) (link)

  • Cell Rep: iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons (link)

  • Stem Cells Dev: The induction of parathyroid cell differentiation from human induced pluripotent stem cells promoted via TGF-α/EGFR signaling (link)

  • Proc Natl Acad Sci U S A: The mechano-chemical circuit drives skin organoid self-organization (link)

• Translational:

  • Cell Death Discov: Transcriptome-based prediction of drugs, inhibiting cardiomyogenesis in human induced pluripotent stem cells (link)

• Biomaterials:

  • Adv Mater: A Novel Superparamagnetic Multifunctional Nerve Scaffold: Remote Actuation Strategy to Boost in situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair (link)

  • Adv Mater: A Balance Between Inter- and Intra- Microgel Mechanics Governs Stem Cell Viability in Injectable Dynamic Granular Hydrogels (link)

  • Stem Cell Res Ther: Photo-click hydrogels for 3D in situ differentiation of pancreatic progenitors from induced pluripotent stem cells (link)

  • ACS Appl Mater Interfaces: Cell Guiding Multicomponent Nanoyarn Tendon Scaffolds with Tunable Morphology and Flexibility (link)

  • Adv Biol (Weinh): Chondroitin Sulfate Improves Mechanical Properties of Gelatin Hydrogel for Cartilage Regeneration in Rats (link)

  • Nat Commun: Tricolor visible wavelength-selective photodegradable hydrogel biomaterials (link)

Clinical

• Pubs:

  • Knee Surg Sports Traumatol Arthrosc: Autologous minced cartilage repair for chondral and osteochondral lesions of the knee joint demonstrates good postoperative outcomes and low reoperation rates at minimum five-year follow-up (link)

• Corporate:

  • BlueRock Therapeutics: Dopaminergic neuronal cell therapy for Parkinson’s Disease: results from a phase 1 study of Bemdaneprocel (link)

  • Abeona: Abeona Therapeutics Announces Positive Pre-BLA Meeting with FDA for EB-101 and Plans for BLA Submission (link)

• Newly posted studies:

  • NCT06021067: Dead Mesenchymal Stem Cells for Radiation Lung Injury (link)

  • NCT06013423: Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With High-Risk Hematologic Diseases (link)

Other (Articles, Perspectives, etc.)

• Nature: A DIY ‘bionic pancreas’ is changing diabetes care — what's next? (link)

• Business:

  • WSJ: Saudi Arabia Is Dangling Billions for Research on Aging. Scientists Are Lining Up to Take It. (link)

  • Endpoints: Exclusive: Stem cell scientist and bit.bio founder launches new startup with goal of extending healthspan by 20 years (link)

  • Epigenic Therapeutics: Epigenic Therapeutics Announces $32 Million in Series A Funding to Bring Breakthrough Epigenome Medicine to Clinical Development (link)

  • Endpoints: Sana lays off staff as cell therapy biotech awaits first clinical data (link)

  • Nat Rev Drug Discov: The company landscape for artificial intelligence in large-molecule drug discovery (link)

• Other interesting papers:

  • Nat Biotechnol: Imaging brain tissue architecture across millimeter to nanometer scales (link)

  • Nat Med: Sex differences in brain protein expression and disease (link)

  • JAMA: Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial (link)

First, know what you want out of the PhD. This is likely easier the further you are in the program, and Nature calls this “Soul-searching before job hunting”. Determine whether it is your advisor, department, or academia you do not enjoy before leaping to industry. Maybe a Senior Scientist position is ideal if you love the research but hate grant writing and clawing through 40 post-docs before becoming an adjunct, but maybe being a professor/PI with their own lab will help you craft an environment you love. Or maybe you just want to hard pivot away from the bench.

Second, build your cache. Nature calls this “Building social capital” but applies it more to social media. I advise also cold-emailing, -calling, -LinkedIn(ing?) people in a variety of industries that interest you. I reached out to people in big pharma, small biotech, finance, and consulting before landing on a career path, but I was also late to the game and felt I needed to catch up. The sooner you know you do not want to be in academia, the sooner you can start the targeted hunt for your career beginnings including summer internships or sitting in on/auditing classes.

Last, make yourself marketable while breathing freely. The risk of burnout is real in these programs, and admitting “failure” (a poor word choice IMO) at dropping out is only recently catching on. Accomplishing and learning things in different fields during your PhD can be rewarding for your career and also your mental health. For example, I used the business school’s Bloomberg terminals to learn the finances of pharma; a lab colleague used her chemistry knowledge to try new recipes (truly reminiscent of Lessons in Chemistry).

There is no one path out of the lab, and your passions may bring you right back to academia - there is nothing wrong with that. If you’re thinking about a PhD, do not let the doomers get to your head; similarly, if you want out do not let your department bully you in to a post-doc.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Circulation: Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus (link)

Background: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use.

Methods: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models.

Results: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism.

Conclusions: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.

Glia: Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS (link)

Remyelination failure is considered a major obstacle in treating chronic-progressive multiple sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need for a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models. We examined PD0325901 effects in the chronically inflamed central nervous system. Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive experimental autoimmune encephalomyelitis with PD0325901 showed no clinical improvement in comparison to the control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC. Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.

Adv Healthc Mater: A Pillar and Perfusion Plate Platform for Robust Human Organoid Culture and Analysis (link)

Human organoids have potential to revolutionize in vitro disease modeling by providing multicellular architecture and function that are similar to those in vivo. This innovative and evolving technology, however, still suffers from assay throughput and reproducibility to enable high-throughput screening (HTS) of compounds due to cumbersome organoid differentiation processes and difficulty in scale-up and quality control. Using organoids for HTS is further challenged by lack of easy-to-use fluidic systems that are compatible with relatively large organoids. Here, we overcome these challenges by engineering "microarray three-dimensional (3D) bioprinting" technology and associated pillar and perfusion plates for human organoid culture and analysis. High-precision, high-throughput stem cell printing and encapsulation techniques were demonstrated on a pillar plate, which was coupled with a complementary deep well plate and a perfusion well plate for static and dynamic organoid culture. Bioprinted cells and spheroids in hydrogels were differentiated into liver and intestine organoids for in situ functional assays. The pillar/perfusion plates are compatible with standard 384-well plates and HTS equipment, and thus may be easily adopted in current drug discovery efforts.

Stem cells / RegenMed

• FASEB J: Inhibition of CK2α accelerates skin wound healing by promoting endothelial cell proliferation through the Hedgehog signaling pathway (link)

• Autophagy: Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation (link)

• Adv Healthc Mater: Telomerase Mrna Enhances Human Skin Engraftment for Wound Healing (link)

• J Cereb Blood Flow Metab: Preconditioning with interleukin-1 alpha is required for the neuroprotective properties of mesenchymal stem cells after ischaemic stroke in mice (link)

• Stem Cells Transl Med: Human Spinal Oligodendrogenic Neural Progenitor Cells Enhance Pathophysiological Outcomes and Functional Recovery in a Clinically Relevant Cervical Spinal Cord Injury Rat Model (link)

• JCI Insight: HSPB2 facilitates neural regeneration through autophagy for sensorimotor recovery after traumatic brain injury (link)

• J Heart Lung Transplant: Pleiotropic effects of extracellular vesicles from induced pluripotent stem cell-derived cardiomyocytes on ischemic cardiomyopathy: A pre-clinical study (link)

• Stem Cell Res Ther: Soluble CX3CL1-expressing retinal pigment epithelium cells protect rod photoreceptors in a mouse model of retinitis pigmentosa (link)

• Arthritis Rheumatol: TET1 regulates skeletal stem cell (SSC) mediated cartilage regeneration (link)

• Reviews:

  • Stem Cell Res Ther: Dedifferentiated fat cells: current applications and future directions in regenerative medicine (link)

  • Curr Opin Genet Dev: Reprogramming of pancreatic islet cells for regeneration and rejuvenation (link)

Aging / Longevity

• Translational:

  • Elife: Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans (link)

  • Aging Cell: Accelerated aging in mice with astrocytic redox imbalance as a consequence of SOD2 deletion (link)

  • Nature: Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice (link)

• Organ- and disease-specific:

  • Science: Aging impairs the neurovascular interface in the heart (link)

  • Nat Commun: Environmental and genetic predictors of human cardiovascular ageing (link)

  • J Am Heart Assoc: Age-Associated Changes in Endothelial Transcriptome and Epigenetic Landscapes Correlate With Elevated Risk of Cerebral Microbleeds (link)

  • Aging Cell: Suppression of FOXO1 attenuates inflamm-aging and improves liver function during aging (link)

  • Geroscience: DNA methylation age acceleration contributes to the development and prediction of non-alcoholic fatty liver disease (link)

  • Cell Rep: Pleiotrophin ameliorates age-induced adult hippocampal neurogenesis decline and cognitive dysfunction (link)

  • Aging Cell: Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects (link)

  • Elife: Hypoxia-inducible factor 1 signaling drives placental aging and can provoke preterm labor (link)

  • J Cell Mol Med: The rejuvenating influence of young plasma on aged intestine (link)

• Other:

  • Aging Cell: Targeted sequencing of the 9p21.3 region reveals association with reduced disease risks in Ashkenazi Jewish centenarians (link)

  • Sci Rep: Line-field confocal optical coherence tomography coupled with artificial intelligence algorithms to identify quantitative biomarkers of facial skin ageing (link)

  • Geroscience: Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults (link)

• Reviews:

  • Semin Immunol: T cell control of inflammaging (link)

  • J Cell Mol Med: Challenges in anti-aging medicine-trends in biomarker discovery and therapeutic interventions for a healthy lifespan (link)

Model systems / Protocols

• Models:

  • Adv Biol (Weinh): Study Transportation of Drugs within Newly Established Murine Colon Organoid Systems (link)

  • Sci Adv: An engineered Sox17 induces somatic to neural stem cell fate transitions independently from pluripotency reprogramming (link)

• Translational:

  • Adv Exp Med Biol: Recellularization of Acellular Xeno Kidney Scaffold: An In Vivo Method to Generate Bioartificial Kidney (link)

  • Proc Natl Acad Sci U S A: Immune-infiltrated kidney organoid-on-chip model for assessing T cell bispecific antibodies (link)

  • Stem Cells: Automated generation of hiPSC-derived hepatic progeny by cost-efficient compounds (link)

  • Sci Rep: Development of a three-dimensional organoid model to explore early retinal phenotypes associated with Alzheimer's disease (link)

  • Tissue Eng Regen Med: Enhancing Viability of Human Embryonic Stem Cells during Cryopreservation via RGD-REP-Mediated Activation of FAK/AKT/FoxO3a Signaling Pathway (link)

  • Stem Cells: Improved cryopreservation of human induced pluripotent stem cell (iPSC) and iPSC derived neurons using ice-recrystallization inhibitors (link)

• Biomaterials:

  • Biofabrication: A scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds (link)

  • Adv Healthc Mater: A Biodegradable, Adhesive and Stretchable Hydrogel and Potential Applications for Allergic Rhinitis and Epistaxis (link)

  • Adv Mater: Diels-Alder Photoclick Patterning of Extracellular Matrix for Spatially Controlled Cell Behaviors (link)

  • Biomed Mater: Triaxial bioprinting large-size vascularized constructs with nutrient channels (link)

  • Biomed Mater: Human adipose-derived mesenchymal stem cells laden in gellan gum spongy-like hydrogels for volumetric muscle loss treatment (link)

  • Biomater Sci: Development of digital light processing-based multi-material bioprinting for fabrication of heterogeneous tissue constructs (link)

  • Adv Healthc Mater: Photopolymerizable Hydrogel for Enhanced Intramyocardial Vascular Progenitor Cell Delivery And Post-Myocardial Infarction Healing (link)

Clinical

• Pubs:

  • Stem Cell Res Ther: Combination of adipose-derived stem cell conditioned media and minoxidil for hair regrowth in male androgenetic alopecia: a randomized, double-blind clinical trial (link)

  • Stem Cell Res Ther: Clinical efficacy and safety of multipotent adult progenitor cells (invimestrocel) for acute respiratory distress syndrome (ARDS) caused by pneumonia: a randomized, open-label, standard therapy-controlled, phase 2 multicenter study (ONE-BRIDGE) (link)

  • Aesthetic Plast Surg: Staged Stem Cell-Enriched Tissue (SET) Injections for Soft Tissue Augmentation in Hostile Recipient Areas: A Preliminary Report (link)

  • Curr Stem Cell Res Ther: Efficacy and Safety of Bone Marrow Derived Stem Cell Therapy for Ischemic Stroke: Evidence from Network Meta-analysis (link)

  • Stem Cells Transl Med: Allogeneic Cell Therapy Applications in Neonates: A Systematic Review (link)

  • Adv Nutr: The Safety and Anti-Ageing Effects of Nicotinamide Mononucleotide in Human Clinical Trials: An Update (link)

• Newly posted studies:

  • NCT05999656: Human Cord Blood Mononuclear Cells in the Treatment of Refractory Diabetic Foot (link)

  • NCT06001853: Allogeneic BM-MSC's in Patients With Lumbar Facet Arthropathy (link)

  • NCT06003530: Study for Treatment of Chronic Diabetic Foot Ulcers With the Investigational Allogeneic Cell Therapy Product, hOMSC200 (link)

  • NCT06006052: Regenerative Endodontic in Immature Permanent Teeth (link)

Other (Articles, Perspectives, etc.)

• Nat Biotechnol: Scientists hone tools to measure aging and rejuvenation interventions (link)

• Business:

  • Cellares: Cellares Raises $255M Series C to Launch First Integrated Development and Manufacturing Organization (IDMO) and Pioneering Smart Factory to Meet Global Demand for Life-Saving Cell Therapies (link)

  • WSJ: For This Venture Capitalist, Research on Aging Is Personal; ‘Bob Has a Big Fear of Death’ (link)

  • Endpoints: The Endpoints Slack Interview: NewLimit's Jacob Kimmel brings anti-aging back to reality (link)

• Other interesting papers:

  • Nature: A high-performance speech neuroprosthesis (link)

  • Nat Neurosci: A stable and replicable neural signature of lifespan adversity in the adult brain (link)

  • Nature: The complete sequence of a human Y chromosome (link)

Klotho, named after the Greek fate who spins the thread of life, was first discovered in 1997 by scientists investigating the molecular basis of aging. Klotho acts as a co-receptor for fibroblast growth factor receptors (FGFRs), modulating their activity and influencing various signaling pathways. This interaction plays a crucial role in multiple physiological processes, including phosphate metabolism, calcium homeostasis, and vitamin D regulation. Additionally, Klotho appears to protect against oxidative stress and inflammation, both of which contribute to the aging process. For example, mice lacking the Klotho gene exhibit premature aging, while those with elevated Klotho expression often experience extended lifespans and reduction in age-related decline in cognitive and physical function. Klotho's effects on aging are mediated through its influence on various cellular processes, such as autophagy, apoptosis, and DNA repair.

Evaluate Pharma currently lists 12 companies targeting klotho or klotho beta (klotho beta is more widely expressed), including Klotho Therapeutics, the first company to be founded around developing klotho-targeting therapeutics. Big name companies such as Roche, Merck, and BMS are also looking at klotho, and modalities run the gambit from small molecule agonists to gene therapy and mAbs. Given the wide distribution of klotho, many organ systems and diseases invilved with gaing may be targeted, including ophthalmology, diabetes, kidney disease, and various dementias.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week (focus on platelets)

Nat Aging: Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice (link)

Platelet factors regulate wound healing and can signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein, increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho-and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.

Nat Commun: Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice (link)

The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing.

Nature: Platelet factors attenuate inflammation and rescue cognition in ageing (link)

Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.

Stem cells / RegenMed

• JAMA Surg: Normal Graft Function After Pig-to-Human Kidney Xenotransplant (link)

• Regen Med: Perfusion in vivo bioreactor promotes regeneration of vascularized tissue-engineered bone (link)

• Cell Rep: Synergy of 5-aminolevulinate supplement and CX3CR1 suppression promotes liver regeneration via elevated IGF-1 signaling (link)

• Biol Res: Human umbilical cord mesenchymal stem cells (hUC-MSCs) alleviate paclitaxel-induced spermatogenesis defects and maintain male fertility (link)

• Sci Rep: Adipose-derived mesenchymal stem cell therapy for reverse bleomycin-induced experimental pulmonary fibrosis (link)

• Glia: Brd activity regulates Müller glia-dependent retinal regeneration in zebrafish (link)

• J Immunother: Mesothelin-targeted CAR-NK Cells Derived From Induced Pluripotent Stem Cells Have a High Efficacy in Killing Triple-negative Breast Cancer Cells as Shown in Several Preclinical Models (link)

• Reviews:

  • Physiol Rev: Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing (link)

  • Nat Rev Cardiol: Animal models to study cardiac regeneration (link)

  • Cureus: Biomimetic Approaches in Cardiac Tissue Engineering: Replicating the Native Heart Microenvironment (link)

Aging / Longevity

• Translational:

  • Sci Transl Med: NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates (link)

  • Nat Aging: Tubular lysosome induction couples animal starvation to healthy aging (link)

  • BMC Genomics: Evolutionary analysis of the mTOR pathway provide insights into lifespan extension across mammals (link)

• Organ- and disease-specific:

  • Sci Transl Med: Endothelial FoxM1 reactivates aging-impaired endothelial regeneration for vascular repair and resolution of inflammatory lung injury (link)

  • Sci Rep: Exosomes secreted by mesenchymal stem cells delay brain aging by upregulating SIRT1 expression (link)

  • Aging (Albany NY): Natural aging and ovariectomy induces parallel phosphoproteomic alterations in skeletal muscle of female mice (link)

  • Aging Cell: AAV-Mediated nuclear localized PGC1α4 delivery in muscle ameliorates sarcopenia and aging-associated metabolic dysfunctions (link)

  • Cell Death Dis: BPIFB4 and its longevity-associated haplotype protect from cardiac ischemia in humans and mice (link)

  • J Am Heart Assoc: Arterial Age and Early Vascular Aging, But Not Chronological Age, Are Associated With Faster Thoracic Aortic Aneurysm Growth (link)

• Other:

  • Elife: Epigenetic signature of human immune aging in the GESTALT study (link)

  • Aging Cell: Associations between cardiorespiratory fitness and lifestyle-related factors with DNA methylation-based ageing clocks in older men: WASEDA'S Health Study (link)

• Reviews:

  • Nat Prod Rep: The role of Caenorhabditis elegans in the discovery of natural products for healthy aging (link)

  • Adv Biol (Weinh): Role of Telomeres and Telomerase in Parkinson's Disease-A New Theranostics? (link)

Model systems / Protocols

• Models:

  • Nature: Transient naive reprogramming corrects hiPS cells functionally and epigenetically (link)

  • Biomater Res: A novel and cost-effective method for high-throughput 3D culturing and rhythmic assessment of hiPSC-derived cardiomyocytes using retroreflective Janus microparticles (link)

  • Bioessays: Suicide gene-enabled cell therapy: A novel approach to scalable human pluripotent stem cell quality control (link)

• Translational:

  • STAR Protoc: Protocol to optimize the biobanking of ovarian cancer organoids by accommodating patient-specific differences in stemness potential (link)

• Biomaterials:

  • ACS Nano: Amyloid Fibril and Clay Nanosheet Dual-Nanoengineered DNA Dynamic Hydrogel for Vascularized Bone Regeneration (link)

  • J Control Release: Targeted delivery of CD163+ macrophage-derived small extracellular vesicles via RGD peptides promote vascular regeneration and stabilization after spinal cord injury (link)

  • Adv Healthc Mater: Bone Regeneration in A Large Animal Model Featuring A Modular Off-The-Shelf Soft Callus Mimetic (link)

  • Laryngoscope: Assessing the Biocompatibility and Regeneration of Electrospun-Nanofiber Composite Tracheal Grafts (link)

  • Adv Sci (Weinh): Bone-Targeted Delivery of Cell-Penetrating-RUNX2 Fusion Protein in Osteoporosis Model (link)

  • Adv Healthc Mater: A Novel PTH-Related Peptide Combined with 3d Printed Macroporous Titanium Alloy Scaffold Enhances Osteoporotic Osseointegration (link)

Clinical

• Pubs:

  • Cytotherapy: Marrow-Derived Autologous Stromal Cells for the Restoration of Salivary Hypofunction (MARSH): A pilot, first-in-human study of interferon gamma-stimulated marrow mesenchymal stromal cells for treatment of radiation-induced xerostomia (link)

  • Regen Med: The role of osteoarthritis severity, BMI and age on clinical efficacy of bone marrow aspirate concentrate in the treatment of knee osteoarthritis (link)

  • PLoS One: Adipose derived stromal vascular fraction and fat graft for treating the hands of patients with systemic sclerosis. A randomized clinical trial (link)

• Corporate:

  • Gracell: On track to submit US IND filing for planned Phase 1 trial of FasTCAR-T GC012F in refractory systemic lupus erythematosus (rSLE) in 2023 (link)

  • ImmPACT Bio: ImmPACT Bio Announces FDA Clearance of IND Application for Bispecific CD19/CD20 CAR T Therapy IMPT-514 for the Treatment of Refractory Systemic Lupus Erythematosus (link)

• Newly posted studies:

  • NCT05991986: Preparation of Patient Autologous Induced Pluripotent Stem Cell-derived Retinal Cells for AMD (link)

  • NCT05993884: Safety and Preliminary Efficacy of Allogeneic Endothelial Progenitor Cells (EPCs) in Patients With Acute Ischemic Stroke (link)

  • NCT05993611: Allogeneic CD6 Chimeric Antigen Receptor T Regulatory Cells (CD6-CAR Tregs) for the Treatment of Patients With Chronic Graft Versus Host Disease After Allogeneic Hematopoietic Cell Transplantation (link)

Other (Articles, Perspectives, etc.)

• TIME: A New Technique Uses a Patient's Own Stem Cells to Restore Their Vision (link)

• Artif Organs: Bioethical implications of organ-on-a-chip on modernizing drug development (link)

• Business:

  • Endpoints: SPAC Ashington Innovation plans to acquire dormant biotech Celixir and lead heart failure program for $172M (link)

  • Endpoints: Bayer's cell therapy unit BlueRock Therapeutics lays off about 50 employees (link)

• Other interesting papers:

  • Nature: Mapping the T cell repertoire to a complex gut bacterial community (link)Science: Yolk sac cell atlas reveals multiorgan functions during human early development (link)

  • JAMA Intern Med:Association of Intensive Lifestyle Intervention for Type 2 Diabetes With Labor Market Outcomes (link)papers of the week

What I think is less appreciated - likely due to the catchall term of ‘sexual health’ - is regenerative medicines’ potential upstream, i.e. on the prostate and testes. For example, a paper this week (here) demonstrates reversal of adverse effects on testes from endocrine-disrupting chemicals using VSELs; a review (here) describes the promise of tissue engineering after cancer-associated prostatectomy; and a mini-review (here) discusses stem cell treatments for stress urinary incontinence.

While less than 50% of men will discuss with their doctor (or partner!) about sexual health, it is much more common to seek treatment after surgery since it gives the patient an “out”, or a reason to believe ED or incontinence is not their fault (not that spontaneous development is the man or partner’s fault in the first place). It is important that men get comfortable discussing this topic, and it is promising to see the number of regenerative trials in this arena.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Nat Aging: Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging (link)

The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor ('mvAge'). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1. Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge (P value = 8.41 × 10^-5). Similarly, genetically proxied thiazolidinediones (P value = 3.50 × 10^-10), proprotein convertase subtilisin/kexin 9 inhibition (P value = 1.62 × 10^-6), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.

Aging Cell: The secretome atlas of two mouse models of progeria (link)

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (Lmna^G609G/G609G and Zmpste24^-/- mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging.

Circ Res: CCND2 Modified mRNA Activates Cell Cycle of Cardiomyocytes in Hearts With Myocardial Infarction in Mice and Pigs (link)

Background: Experiments in mammalian models of cardiac injury suggest that the cardiomyocyte-specific overexpression of CCND2 (cyclin D2, in humans) improves recovery from myocardial infarction (MI). The primary objective of this investigation was to demonstrate that our specific modified mRNA translation system (SMRTs) can induce CCND2 expression in Cardiomyocytes and replicate the benefits observed in other studies of cardiomyocyte-specific CCND2 overexpression for myocardial repair.

Methods: The CCND2-cardiomyocyte-specific modified mRNA translation system (cardiomyocyte SMRTs) consists of 2 modRNA constructs: 1 code for CCND2 and contains a binding site for L7Ae, and the other codes for L7Ae and contains recognition elements for the cardiomyocyte-specific microRNAs miR-1 and miR-208. Thus, L7Ae suppresses CCND2 translation in noncardiomyocytes but is itself suppressed by endogenous miR-1 and -208 in cardiomyocytes, thereby facilitating cardiomyocyte-specific CCND2 expression. Experiments were conducted in both mouse and pig models of MI, and control assessments were performed in animals treated with an SMRTs coding for the cardiomyocyte-specific expression of luciferase or GFP, in animals treated with L7Ae modRNA alone or with the delivery vehicle, and in Sham-operated animals.

Results: CCND2 was abundantly expressed in cultured, postmitotic cardiomyocytes 2 days after transfection with the CCND2-cardiomyocyte SMRTs, and the increase was accompanied by the upregulation of markers for cell-cycle activation and proliferation (eg, Ki67 and Aurora B kinase). When the GFP-cardiomyocyte SMRTs were intramyocardially injected into infarcted mouse hearts, the GFP signal was observed in cardiomyocytes but no other cell type. In both MI models, cardiomyocyte proliferation (on day 7 and day 3 after treatment administration in mice and pigs, respectively) was significantly greater, left-ventricular ejection fractions (days 7 and 28 in mice, days 10 and 28 in pigs) were significantly higher, and infarcts (day 28 in both species) were significantly smaller in animals treated with the CCND2-cardiomyocyte SMRTs than in any other group that underwent MI induction.

Conclusions: Intramyocardial injections of the CCND2-cardiomyocyte SMRTs promoted cardiomyocyte proliferation, reduced infarct size, and improved cardiac performance in small and large mammalian hearts with MI.

Obesity (Silver Spring): Myogenically differentiated mesenchymal stem cell insulin sensitivity is associated with infant adiposity at 1 and 6 months of age (link)

Objective: In adults, skeletal muscle insulin sensitivity (S_I ) and fatty acid oxidation (FAO) are linked with a predisposition to obesity. The current study aimed to determine the effects of maternal exercise on a model of infant skeletal muscle tissue (differentiated umbilical cord mesenchymal stem cells [MSCs]) S_I and FAO and analyzed for associations with infant body composition.

Methods: Females <16 weeks' gestation were randomized to either 150 min/wk of moderate-intensity aerobic, resistance, or combination exercise or a nonexercising control. At delivery, MSCs were isolated from umbilical cords and myogenically differentiated, and S_I and FAO were measured using radiolabeled substrates. Infant body fat percentage (BF%) and fat-free mass were calculated using standard equations at 1 and 6 months of age.

Results: MSCs from infants of all exercisers had significantly (p < 0.05) higher S_I . MSC S_I was inversely associated with infant BF% at 1 (r = -0.38, p < 0.05) and 6 (r = -0.65, p < 0.01) months of age. Infants with high S_I had lower BF% at 1 (p = 0.06) and 6 (p < 0.01) months of age. MSCs in the high S_I group had higher (p < 0.05) FAO.

Conclusions: Exposure to any type of exercise in utero improves offspring S_I and could reduce adiposity in early infancy.

Stem cells / RegenMed

• Sci Transl Med: The oncomodulin receptor ArmC10 enables axon regeneration in mice after nerve injury and neurite outgrowth in human iPSC-derived sensory neurons (link)

• Cell Rep: Rescue of Alzheimer's disease phenotype in a mouse model by transplantation of wild-type hematopoietic stem and progenitor cells (link)

• Cytotherapy: Bone marrow-derived mononuclear cells ameliorate neurological function in chronic cerebral infarction model mice via improvement of cerebral blood flow (link)

• Osteoarthritis Cartilage: Basic fibroblast growth factor promotes meniscus regeneration through the cultivation of synovial mesenchymal stem cells via the CXCL6-CXCR2 pathway (link)

• FASEB J: Hmga1-overexpressing lentivirus protects against osteoporosis by activating the Wnt/β-catenin pathway in the osteogenic differentiation of BMSCs (link)

• Stem Cell Res Ther: Mesenchymal stem cells shift the pro-inflammatory phenotype of neutrophils to ameliorate acute lung injury (link)

• Cell Prolif: Apoptotic bodies inhibit inflammation by PDL1-PD1-mediated macrophage metabolic reprogramming (link)

• Regen Med: Effects of transplantation of umbilical cord blood mononuclear cells into the scrotum on sexual function in elderly mice (link)

• Proc Natl Acad Sci U S A: DNA methylation in the mouse cochlea promotes maturation of supporting cells and contributes to the failure of hair cell regeneration (link)

• Nat Commun: Cas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing (link)

• Xenotransplantation: Transplantation of porcine adrenal spheroids for the treatment of adrenal insufficiency (link)

• Reviews:

  • Stem Cell Res Ther: Neural stem cell-derived exosomes and regeneration: cell-free therapeutic strategies for traumatic brain injury (link)

  • Regen Med: Keeping an eye on sustainable regeneration (link)

  • Stem Cell Rev Rep: Stem cell Derived Extracellular Vesicles to Alleviate ischemia-reperfusion Injury of Transplantable Organs. A Systematic Review (link)

  • FEBS J: Hepatocyte reprogramming in liver regeneration: biological mechanisms and applications (link)

Aging / Longevity

• Translational:

  • Aging Cell: Downregulation of Krüppel-like factor 14 accelerated cellular senescence and aging (link)

  • ISME J: Gut microbial genetic variation modulates host lifespan, sleep, and motor performance (link)

  • Angiogenesis: Aging impairs the ability of vascular endothelial stem cells to generate endothelial cells in mice (link)

• Organ- and disease-specific:

  • J Cachexia Sarcopenia Muscle: AAV1.NT-3 gene therapy in the SOD1KO mouse model of accelerated sarcopenia (link)

  • J Gerontol A Biol Sci Med Sci: Counteracting age-related Netrin-1 signaling insufficiency ameliorates endothelial cell senescence and angiogenesis impairment (link)

• Other:

  • Nat Aging: Universal DNA methylation age across mammalian tissues (link)

  • Clin Epigenetics: Introduction of a multiplex amplicon sequencing assay to quantify DNA methylation in target cytosine markers underlying four selected epigenetic clocks (link)

  • Clin Epigenetics: Global effects of identity and aging on the human sperm methylome (link)

  • Mov Disord: DNA Methylation Age Acceleration Is Not Associated with Age of Onset in Parkinson's Disease (link)

  • Psychol Med: Associations between polygenic risk scores and accelerated brain ageing in smokers (link)

• Reviews:

  • Geroscience: Geroprotective potential of microbiome modulators in the Caenorhabditis elegans model (link)

Model systems / Protocols

• Models:

  • Nat Biomed Eng: Electro-metabolic coupling in multi-chambered vascularized human cardiac organoids (link)

  • APL Bioeng: Direct differentiation of human pluripotent stem cells into vascular network along with supporting mural cells (link)

  • Life Sci Alliance: Generating fast-twitch myotubes in vitro with an optogenetic-based, quantitative contractility assay (link)

  • NPJ Regen Med: Transgene-free direct conversion of murine fibroblasts into functional muscle stem cells (link)

  • SLAS Technol: Automated cell culture system for the production of cell aggregates with growth plate-like structure from induced pluripotent stem cells (link)

• Translational:

  • IEEE Trans Nanobioscience: COTiR: Molecular Communication Model for Synthetic Exosome-based Tissue Regeneration (link)

  • J Adv Res: Modifications of Lipid Pathways Restrict SARS-CoV-2 Propagation in Human Induced Pluripotent Stem Cell-derived 3D Airway Organoids (link)

• Biomaterials:

  • Nat Nanotechnol: Dynamic matrices with DNA-encoded viscoelasticity for cell and organoid culture (link)

  • Acta Biomater: Injectable decellularized extracellular matrix hydrogel promotes salivary gland regeneration via endogenous stem cell recruitment and suppression of fibrogenesis (link)

  • Food Chem: Programmable scaffolds with aligned porous structures for cell cultured meat (link)

Clinical

• Pubs:

  • J Am Soc Nephrol: Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M Cell) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM) (link)

  • Bone Marrow Transplant: Placental expanded mesenchymal-like cells (PLX-R18) for poor graft function after hematopoietic cell transplantation: A phase I study (link)

  • Arthritis Res Ther: Effect of intra-knee injection of autologous adipose stem cells or mesenchymal vascular components on short-term outcomes in patients with knee osteoarthritis: an updated meta-analysis of randomized controlled trials (link)

  • Orthop J Sports Med: Five-Year Outcomes After Implantation of a Scaffold-Free Tissue-Engineered Construct Generated From Autologous Synovial Mesenchymal Stromal Cells for Repair of Knee Chondral Lesions (link)

  • Ther Innov Regul Sci: Statistical Evaluation of Responder Analysis in Stem Cell Clinical Trials (link)

• Corporate:

  • Aspen Neuro: Aspen Neuroscience Announces FDA Clearance of Investigational New Drug Application for ANPD001, Autologous Cell Therapy for the Treatment of Parkinson’s Disease (link)

• Newly posted studies:

  • NCT05982054: Bone Marrow Cells With Core Decompression for AVN Treatment (link)

  • NCT05984628: Umbilical Cord Stem Cells for Skin Grafts in Donor Site Wounds (link)

  • NCT05983627: Safety and Tolerance of Umbilical Cord Mesenchymal Stem Cells in Patients With Acute Respiratory Distress Syndrome (link)

  • NCT05984303: Human Umbilical Cord-derived Mesenchymal Stem Cells for Decompensated Cirrhosis (MSC-DLC-1b) (link)

Other (Articles, Perspectives, etc.)

• Stem Cell Reports: Special Editorial, Forum, and Perspective articles on access to stem cell therapies

• Business:

  • Regeneron: Regeneron to Acquire Decibel Therapeutics, Strengthening Gene Therapy and Hearing Loss Programs (link)

  • Addimmune: Addimmune, a Clinical Stage Hiv-Focused Gene Therapy Company, to go Public Through Business Combination With 10x Capital Venture Acquisition Corp. III (link)

  • Regen Med: Industry updates from the field of stem cell research and regenerative medicine in June 2023 (link)

• Other interesting papers:

  • Science: DNA methylation networks underlying mammalian traits (link

  • JAMA Netw Open: Probability of 5% or Greater Weight Loss or BMI Reduction to Healthy Weight Among Adults With Overweight or Obesity (link)

  • Eur J Prev Cardiol: The association between daily step count and all-cause and cardiovascular mortality: a meta-analysis (link)

  • Sci Rep: Supervised machine learning classification of psychosis biotypes based on brain structure: findings from the Bipolar-Schizophrenia network for intermediate phenotypes (B-SNIP)  (link)

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

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Happy August!

There's lots on my mind to want to talk about, but in the interest of it being exhaustingly hot, I'll keep this concise enough 

1. You know I can't go a month without finding some significance in how we're connected with our environment: yesterday Aug 1 was Lughnasa: the Gaelic holiday that celebrates the mid-point between summer and fall. It is full-on harvest season, and observances typically include the celebration of abundance, and recognizing how much we have to harvest from the seeds we planted at the beginning of spring. That was over 4 months ago! What in your life has reached its peak growth, and in what ways can you enjoy the fruits of your labor so far?

2. In alignment with gardens popping off, I thought I'd break down a few benefits of eating seasonally (and with that, locally):

• Taste - IYKYK. If you don't, just trust. (It's corn season!)

• Nutrients - Fruits, vegetables, and herbs that are picked and eaten right away provide the most nutrients. By the time a food from hundreds/thousands of miles away is finally eaten, it's lost a lot of the nutrients that kept it thriving before being harvested.

  • there's also the concept of prana, which in Sanscrit simply translates to "life force energy." When we eat something immediately taken from its source of life, it is still teaming with that energy. 

• Gut health - Local produce means we are being exposed to the bacteria in local dirt, which is hugely beneficial for the bacteria in our gut. If it sounds familiar, it's a similar concept to having local honey during allergy season so we're exposed at low doses to the allergens that are affecting us.

• Cost - Usually in-season produce that is local enough is cheaper. 

• Ze earth - As you can imagine, it's more environmentally friendly to consume something that took a lot less energy to get into your grocery bag.

I could go on about both of these topics, but hopefully it's a good jump start to continuing any more learning! I recommend signing up for daily emails from the Farmer's Almanac - they always have seasonal recipes, gardening advice, and cool info like a list of edible flowers. Almost every day, they answer a question I had just been wondering about.

In Health,

Sam

Top papers of the week

Biogerontology: Evaluation of potential aging biomarkers in healthy individuals: telomerase, AGEs, GDF11/15, sirtuin 1, NAD+, NLRP3, DNA/RNA damage, and klotho (link)

Aging is a natural process of gradual decrease in physical and mental capacity. Biological age (accumulation of changes and damage) and chronological age (years lived) may differ. Biological age reflects the risk of various types of disease and death from any cause. We selected potential biomarkers of aging - telomerase, AGEs, GDF11 and 15 (growth differentiation factor 11/15), sirtuin 1, NAD+ (nicotinamide adenine dinucleotide), inflammasome NLRP3, DNA/RNA damage, and klotho to investigate changes in their levels depending on age and sex. We included 169 healthy volunteers and divided them into groups according to age (under 35; 35-50; over 50) and sex (male, female; male and female under 35; 35-50, over 50). Markers were analyzed using commercial ELISA kits. We found differences in values depending on age and gender. GDF15 increased with age (under 30 and 35-50 p < 0.002; 35-50 and over 50; p < 0.001; under 35 and over 50; p < 0.001) as well as GDF11 (35-50 and over 50; p < 0.03; under 35 and over 50; p < 0.02), AGEs (under 30 and 35-50; p < 0.005), NLRP3 (under 35 over 50; p < 0.03), sirtuin 1 (35-50 and over 50; p < 0.0001; under 35 and over 50; p < 0.004). AGEs and GDF11 differed between males and females. Correlations were identified between individual markers, markers and age, and markers and sex. Markers that reflect the progression of biological aging vary with age (GDF15, GDF11, AGEs, NLRP3, sirtuin) and sex (AGEs, GDF11). Their levels could be used in clinical practice, determining biological age, risk of age-related diseases and death of all-causes, and initiating or contraindicating a therapy in the elderly based on the patient's health status.

Nature: cGAS-STING drives ageing-related inflammation and neurodegeneration (link)

Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.

Nat Commun: Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures (link)

Plasmodium falciparum (Pf) parasite development in liver represents the initial step of the life-cycle in the human host after a Pf-infected mosquito bite. While an attractive stage for life-cycle interruption, understanding of parasite-hepatocyte interaction is inadequate due to limitations of existing in vitro models. We explore the suitability of hepatocyte organoids (HepOrgs) for Pf-development and show that these cells permitted parasite invasion, differentiation and maturation of different Pf strains. Single-cell messenger RNA sequencing (scRNAseq) of Pf-infected HepOrg cells has identified 80 Pf-transcripts upregulated on day 5 post-infection. Transcriptional profile changes are found involving distinct metabolic pathways in hepatocytes with Scavenger Receptor B1 (SR-B1) transcripts highly upregulated. A novel functional involvement in schizont maturation is confirmed in fresh primary hepatocytes. Thus, HepOrgs provide a strong foundation for a versatile in vitro model for Pf liver-stages accommodating basic biological studies and accelerated clinical development of novel tools for malaria control.

Stem cells / RegenMed

• Stem Cell Rev Rep: MSC-Derived Exosomes Ameliorate Intervertebral Disc Degeneration By Regulating the Keap1/Nrf2 Axis (link)

• Am J Physiol Lung Cell Mol Physiol: Complex Urban Atmospheres alters Alveolar Stem Cells Niche Properties and drives Lung Fibrosis (link)

• Stem Cell Res Ther: Hybrid spheroids containing mesenchymal stem cells promote therapeutic angiogenesis by increasing engraftment of co-transplanted endothelial colony-forming cells in vivo (link)

• Am J Sports Med: Donor-Matched Peripheral Blood-Derived Mesenchymal Stem Cells Combined With Platelet-Rich Plasma Synergistically Ameliorate Surgery-Induced Osteoarthritis in Rabbits: An In Vitro and In Vivo Study (link)

• Tissue Eng Regen Med: Multiple Injections of Adipose-Derived Stem Cells Improve Graft Survival in Human-to-Rat Skin Xenotransplantation through Immune Modulation (link)

• Mol Ther: Single-cell dissection of cellular and molecular features underlying mesenchymal stem cell therapy in ischemic acute kidney injury (link)

• Curr Stem Cell Res Ther: TNF-α pretreated hematopoietic stem cells inhibit the migration and inflammatory response of HUVECs and attenuate GVHD (link)

• Reviews:

  • Cell Regen: Advanced cryopreservation engineering strategies: the critical step to utilize stem cell products (link)

  • Cell Commun Signal: The role of MSCs and CAR-MSCs in cellular immunotherapy (link)

  • Adv Sci (Weinh): Arthritic Microenvironment-Dictated Fate Decisions for Stem Cells in Cartilage Repair (link)

Aging / Longevity

• Aging Dis: Promoting Healthy Aging: Insights on Brain and Physiological Health - A Special Issue (link)

• Translational:

  • Stem Cell Res Ther: Anti-aging mechanism of different age donor-matched adipose-derived stem cells (link)

  • Nat Commun: Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton (link)

  • Proc Natl Acad Sci U S A: Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans (link)

• Organ- and disease-specific:

  • J Neuroinflammation: ATP-P2X7R-mediated microglia senescence aggravates retinal ganglion cell injury in chronic ocular hypertension (link)

  • J Gerontol A Biol Sci Med Sci: Single Cell Mapping of Large and Small Arteries during Hypertensive Aging (link)

  • Immun Ageing: Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection (link)

  • Am J Physiol Cell Physiol: Age-related Decline in Bone Mineral Transport and Bone Matrix Proteins in Osteoblasts from Stromal Stem Cells (link)

• Other:

  • Eur J Prev Cardiol: Echocardiographic heart ageing patterns predict cardiovascular and non-cardiovascular events and reflect biological age: the SardiNIA study (link)

  • Genome Res: A transcriptome-based single-cell biological age model and resource for tissue-specific aging measures (link)

• Reviews:

  • J Cell Sci: Mechanotransduction through hemidesmosomes during aging and longevity (link)

  • Adv Pharmacol: Senotherapy for lung diseases (link)

Model systems / Protocols

• Models:

  • Adv Healthc Mater: Modeling the Maturation of the Vocal Fold Lamina Propria Using a Bioorthogonally Tunable Hydrogel Platform (link)

  • Cell Death Discov: In vitro oogenesis from murine premeiotic germ cells using a new three-dimensional culture system (link)

• Translational:

  • FEBS Lett: Manipulating and studying gene function in human pluripotent stem cell models (link)

  • Small: Engineered Extracellular Vesicles for Delivery of an IL-1 Receptor Antagonist Promote Targeted Repair of Retinal Degeneration (link)

• Biomaterials:

  • Sci Transl Med: Proregenerative extracellular matrix hydrogel mitigates pathological alterations of pelvic skeletal muscles after birth injury (link)

  • Biomacromolecules: Biophysical Electrical and Mechanical Stimulations for Promoting Chondrogenesis of Stem Cells on PEDOT:PSS Conductive Polymer Scaffolds (link)

  • Mil Med Res: The marriage of immunomodulatory, angiogenic, and osteogenic capabilities in a piezoelectric hydrogel tissue engineering scaffold for military medicine (link)

  • Adv Sci (Weinh): Materials and Design Approaches for a Fully Bioresorbable, Electrically Conductive and Mechanically Compliant Cardiac Patch Technology (link)

  • Biotechnol Bioeng: Stable hydrogel adhesion to polydimethylsiloxane enables cyclic mechanical stimulation of 3D-bioprinted smooth muscle constructs (link)

Clinical

• Pubs:

  • Sci Rep: Effectiveness and safety of normoxic allogenic umbilical cord mesenchymal stem cells administered as adjunctive treatment in patients with severe COVID-19 (link)

  • Minerva Med: Recipients with acute myeloid leukemia with a long telomere and donors with a short telomere have a higher relapse rate within 1-year post-transplantation (link)

  • J Thorac Cardiovasc Surg: Safety and Feasibility of Adjunct Autologous Cord Blood Stem Cell Therapy During the Norwood Heart Operation (link)

  • Vascular: Evaluation of the lower extremity blood supply in no-option critical limb ischemia patients with stem cell transplantation by time maximum intensity projection CT perfusion: A single-centre prospective study (link)

  • Stem Cells Transl Med: Long-Term Safety of Bone Regeneration Using Autologous Stromal Vascular Fraction and Calcium Phosphate Ceramics: A 10-Year Prospective Cohort Study (link)

• Corporate:

  • Endpoints: Vertex doses first patient with next type 1 diabetes cell therapy program, while padding its coffers with strong Q2 (link)

• Newly posted studies:

  • NCT05971342: The Safety and Efficacy of Alveolar Bone Defect Repair Induced by Gelatin Sponge-loaded Apoptotic Vesicle Complex (link)

  • NCT05967325: SVF Combined With Functional Self-assembling Peptide Nanofiber Hydrogels in the Treatment of Spinal Cord Injury (link)

  • NCT05969275: Umbilical Mesenchymal Stromal Cells as Cellular Immunotherapy for Septic Shock (UC-CISSII) (link)

  • NCT05969717: Induced Pluripotent Stem Cell Derived Exosomes for the Treatment of Atopic Dermatitis (link)

Other (Articles, Perspectives, etc.)

• Cytotherapy: International Society for Cell & Gene Therapy Position Paper: Key considerations to support evidence-based cell and gene therapies and oppose marketing of unproven products (link)

• Business:

  • Kyverna: Kyverna Therapeutics Extends Series B Financing Round to $145 Million and Brings in New Investors (link)

  • Epiterna: Epiterna, a Swiss human and pet longevity startup, raised €10M from Prima Materia (link)

  • bit.bio: BlueRock Therapeutics and bit.bio announce collaboration (link)

  • JAMA: Private Equity Ownership in Health Care Linked to Higher Costs, Worse Quality (link)

• Other interesting papers:

  • Nat Commun: Genetic insights into resting heart rate and its role in cardiovascular disease (link)

  • J Gen Intern Med: Adverse Childhood Experiences and Aging-Associated Functional Impairment in a National Sample of Older Community-Dwelling Adults (link)

  • J Neurosci: Boosting serotonin increases information gathering by reducing subjective cognitive costs (link)

  • Nat Commun: Three-dimensional molecular architecture of mouse organogenesis (link)

For example, NLRP3 plays a significant role in the realm of chronic inflammatory disorders such as gout, a painful arthritis caused by the accumulation of uric acid crystals in joints. Inhibition of NLRP3 could offer a promising therapeutic approach to alleviate the severity and frequency of gout attacks by curbing the excessive inflammatory response triggered by the inflammasome. In the field of neurology (my current area of fascination), mounting evidence suggests the involvement of NLRP3 in neuroinflammatory diseases such as Alzheimer's. Neuroinflammation driven by NLRP3 activation exacerbates neuronal damage and contributes to cognitive decline; targeting NLRP3 could potentially mitigate neuroinflammation and offer a novel therapeutic strategy.

Several companies have recognized the therapeutic potential of inhibiting NLRP3: IFM Therapeutics, which is working on developing selective NLRP3 antagonists for the treatment of inflammatory diseases, including gout and atherosclerosis; BioAge, a longevity- and aging-focused company with two NRLP3 inhibitor formulations in opthalmology and CNS disorders; and Inflazome, acquired by Roche for $451M, that focused on developing small-molecule inhibitors of the NLRP3 inflammasome to address a wide range of diseases, including neuroinflammatory conditions and metabolic disorders like type 2 diabetes.

There are a couple papers this week focused on NLRP3 (here, here), but the first published paper mentioning NLRP3 (according to PubMed) was this Nature Genetics paper on familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Since that 2001 paper, every year has seen increasing numbers of publications mentioning NLRP3 with over 3,300 results in 2022 (and on track for over 3,600 in 2023). We have at least one approved IL-1β therapy (Ilaris [canakinumab]), and it’s only a matter of time before we move upstream to successfully target NLRP3.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Nat Aging: Multi-omic rejuvenation and life span extension on exposure to youthful circulation (link)

Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on biological age and long-term health is unknown. Here we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the epigenetic age of blood and liver based on several clock models using two independent platforms. Remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a global multi-omic rejuvenation effect. In addition, old HPB mice showed gene expression changes opposite to aging but akin to several life span-extending interventions. Altogether, we reveal that long-term HPB results in lasting epigenetic and transcriptome remodeling, culminating in the extension of life span and health span.

Nature: Evolutionarily divergent mTOR remodels translatome for tissue regeneration (link)

An outstanding mystery in biology is why some species, such as the axolotl, can regenerate tissues whereas mammals cannot1. Here, we demonstrate that rapid activation of protein synthesis is a unique feature of the injury response critical for limb regeneration in the axolotl (Ambystoma mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components that are selectively activated at the level of translation from pre-existing messenger RNAs in response to injury. By contrast, protein synthesis is not activated in response to non-regenerative digit amputation in the mouse. We identify the mTORC1 pathway as a key upstream signal that mediates tissue regeneration and translational control in the axolotl. We discover unique expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR (axmTOR) in human cells, we show that these changes create a hypersensitive kinase that allows axolotls to maintain this pathway in a highly labile state primed for rapid activation. This change renders axolotl mTOR more sensitive to nutrient sensing, and inhibition of amino acid transport is sufficient to inhibit tissue regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in a highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.

Small: Shape-Configurable Mesh for Hernia Repair by Synchronizing Anisotropic Body Motion (link)

Continuous progress has been made in elucidating the relationship between material property, device design, and body function to develop surgical meshes. However, an unmet need still exists wherein the surgical mesh can handle the body motion and thereby promote the repair process. Here, the hernia mesh design and the advanced polymer properties are tailored to synchronize with the anisotropic abdominal motion through shape configuration. The thermomechanical property of shape configurable polymer enables molding of mesh shape to fit onto the abdominal structure upon temperature shift, followed by shape fixing with the release of the heat energy. The microstructural design of mesh is produced through finite element modeling to handle the abdominal motion efficiently through the anisotropic longitudinal and transverse directions. The design effects are validated through in vitro, ex vivo, and in vivo mechanical analyses using a self-configurable, body motion responsive (BMR) mesh. The regenerative function of BMR mesh leads to effective repair in a rat hernioplasty model by effectively handling the anisotropic abdomen motion. Subsequently, the device-tissue integration is promoted by promoting healthy collagen synthesis with fibroblast-to-myofibroblast differentiation. This study suggests a potential solution to promote hernia repair by fine-tuning the relationship between material property and mesh design.

Stem cells / RegenMed

• Nat Commun: Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI (link)

• Adv Sci (Weinh): hESC-Derived Epicardial Cells Promote Repair of Infarcted Hearts in Mouse and Swine (link)

• J Transl Med: Discovery of therapeutic targets for spinal cord injury based on molecular mechanisms of axon regeneration after conditioning lesion (link)

• Neuroreport: Adipose-derived stem cell exosomes ameliorate traumatic brain injury through the NLRP3 signaling pathway (link)

• BJOG: Allogenic umbilical cord-derived mesenchymal stromal cells improve motor function in prenatal surgical repair of myelomeningocele: An ovine model study (link)

• Science: In vivo hematopoietic stem cell modification by mRNA delivery (link)

• Nat Cell Biol: The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates (link)

• Reviews:

  • Cold Spring Harb Perspect Med: Considerations for Developing an Autologous Induced Pluripotent Stem Cell (iPSC)-Derived Retinal Pigment Epithelium (RPE) Replacement Therapy (link)

  • Stem Cells Transl Med: Orchestration of Mesenchymal Stem/Stromal Cells and Inflammation During Wound Healing (link)

  • Stem Cell Rev Rep: Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside (link)

  • Eur Respir Rev: Regenerative and translational medicine in COPD: hype and hope (link)

Aging / Longevity

• Translational:

  • Sci Signal: Decreased nitrosylation of CaMKII causes aging-associated impairments in memory and synaptic plasticity in mice (link)

  • Aging Cell: Astrocyte- and NMDA receptor-dependent slow inward currents differently contribute to synaptic plasticity in an age-dependent manner in mouse and human neocortex (link)

  • Aging Cell: Delayed formation of neural representations of space in aged mice (link)

  • Nat Aging: Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement (link)

  • FASEB J: Convergent alteration of the mesenchymal stem cell heterogeneity in adipose tissue during aging (link)

  • Nat Aging: Olfactory chemosensation extends lifespan through TGF-β signaling and UPR activation (link)

• Organ- and disease-specific:

  • Circ Res: Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women (link)

  • Aging (Albany NY): Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span (link)

• Other:

  • Health Promot Int: Development of a composite healthy ageing score: evidence from middle-to-older aged Australians (link)

  • Aging Cell: The lipidomic correlates of epigenetic aging across the adult lifespan: A population-based study (link)

  • Neurology: Association of APOE ε4 Status With Long-term Declines in Odor Sensitivity, Odor Identification, and Cognition in Older US Adults (link)

  • Geroscience: Systemic inflammation and biological aging in the Health and Retirement Study (link)

  • Nat Commun: Increasing number of long-lived ancestors marks a decade of healthspan extension and healthier metabolomics profiles (link)

• Reviews:

  • Aging Cell: Circadian regulation in aging: Implications for spaceflight and life on earth (link)

  • Aging Cell: Interactions between mitochondrial dysfunction and other hallmarks of aging: Paving a path toward interventions that promote healthy old age (link)

  • Eur J Pharmacol: Research progress of NLRP3 inflammasome and its inhibitors with aging diseases (link)

Model systems / Protocols

• Models:

  • Lab Chip: Protruding cantilever microelectrode array to monitor the inner electrical activity of cerebral organoids (link)

  • Lab Chip: A controllable perfusion microfluidic chip for facilitating the development of retinal ganglion cells in human retinal organoids (link)

  • Stem Cell Res Ther: Development of a robust induced pluripotent stem cell atrial cardiomyocyte differentiation protocol to model atrial arrhythmia (link)

• Translational:

  • Sci Transl Med: Pharmaco-proteogenomic characterization of liver cancer organoids for precision oncology (link)

  • Nat Immunol: Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro (link)

• Biomaterials:

  • Biofabrication: The bioengineering of perfusable endocrine tissue with anastomosable blood vessels (link)

  • Adv Healthc Mater: Creating And Transferring An Innervated, Vascularized Muscle Flap Made from An Elastic, Cellularized Tissue Construct Developed in Situ (link)

  • J Biol Eng: An injectable, self-healing, electroconductive hydrogel loaded with neural stem cells and donepezil for enhancing local therapy effect of spinal cord injury (link)

  • ACS Appl Mater Interfaces: Nanozyme-Integrated Thermoresponsive In Situ Forming Hydrogel Enhances Mesenchymal Stem Cell Viability and Paracrine Effect for Efficient Spinal Cord Repair (link)

  • Biofabrication: Injectable rBMSCs-laden hydrogel microspheres loaded with naringin for osteomyelitis treatment (link)

  • Biomater Sci: Plasma fibrin membranes loaded with bone marrow mesenchymal stem cells and corneal epithelial cells promote corneal injury healing via attenuating inflammation and fibrosis after corneal burns (link)

  • Sci Rep: A gelatin hydrogel nonwoven fabric improves outcomes of subcutaneous islet transplantation (link)

  • Sci Rep: Human alveolar hydrogels promote morphological and transcriptional differentiation in iPSC-derived alveolar type 2 epithelial cells (link)

  • Nat Mater: Fibre-infused gel scaffolds guide cardiomyocyte alignment in 3D-printed ventricles (link)

Clinical

• Pubs:

  • Lancet Neurol: Soluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: a first-in-human and randomised clinical trial (link)

  • Aging Cell: Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment (link)

  • Stem Cell Res Ther: Dendritic cells mediated by small extracellular vesicles derived from MSCs attenuated the ILC2 activity via PGE2 in patients with allergic rhinitis (link)

  • Regen Med: Effect of platelet-rich plasma on healing of autologous graft after anterior cruciate ligament reconstruction: a randomized control trial (link)

  • Stem Cells Transl Med: Neural Cells for Neurodegenerative Diseases in Clinical Trials (link)

• Corporate:

  • BioCardia: BioCardia Announces DSMB Recommendation to Pause New Enrollment in Phase III Pivotal CardiAMP Cell Therapy Heart Failure Trial While Additional Blinded Data is Collected (link)

  • EpiBone: EpiBone to Start Clinical Trials for Knee Cartilage Grown in Lab (link)

• Newly posted studies:

  • NCT05959902: Effectiveness of Physical Therapy in Stem Cell Transplant Recipients for Knee Osteoarthritis (link)

  • NCT05962931: Clinical Trial With Adipose Tissue Stem Cells on Biological Matrix for the Treatment of Venous Ulcer of the Lower Limbs (link)

  • NCT05962762: Safety and Tolerance of Umbilical Cord Mesenchymal Stem Cells (UC-MSC) in Patients With Ankylosing Spondylitis (link)

Other (Articles, Perspectives, etc.)

• Circulation: FDA Modernization Act 2.0 Paves the Way to Computational Biology and Clinical Trials in a Dish (link)

• Cytotherapy: Cell and gene therapy workforce development: the role of the International Society for Cell & Gene Therapy (ISCT) in the creation of a sustainable and skilled workforce in Europe (link)

• Business:

  • FinSMEs: Ossium Health Raises $52M in Series C Funding (link)

  • Nat Biotechnol: 2Q23 - merger premiums reveal valuation gulf (link)

  • Nat Biotechnol: Drug pipeline 2Q23 - controversy and complexity (link)

• Other interesting papers:

  • Proc Natl Acad Sci U S A: Father's care uniquely influences male neurodevelopment (link)

  • Geroscience: Pan-primate studies of age and sex (link)

  • Nat Rev Genet: Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans (link)

• Crowdfunding: Crowdfunding, as the name implies, involves raising financing from many sources, often with a very small dollar amounts upfront. This method has been very popular for projects that need (tens of) thousands, not millions, to get a project off the ground and has thus not been as attractive for capital-intensive biotech (though unfortunately has been for medical bills). With the advent of AI in healthcare and the low upfronts for spinning tech out of academia, crowdfunding has become a more viable option. Biophysical Therapeutics has done this successfully, raising almost $100k from 43 investors with buyins as low as $100.

• Syndicates/SPVs: A version of crowdfunding specific for accredited investors. AngelList has popularized this method and currently boasts >150 healthcare/biotech syndicates with >1,500 deals. Typical buyins start at $1k and can be up to $5k per deal. Most syndicates/special purpose vehicles receive an allocation alongside VCs and therefore help to fill out the last $100-500k of a funding round; syndicates can also be tapped for this amount via SAFE. CytoReason, backed by Pfizer, allocated space in their most recent round to a syndicate.

• DAOs: Decentralized Autonomous Organizations started as part of the blockchain craze in 2017, and have bled over to the biotech realm due to the open, community-based nature of the org. The process essentially combines crowdfunding with public stock ownership in that every “supporter” (funder) receives voting rights on the direction of the company/pipeline. DAOs can tackle any problem (i.e., VitaDAO for longevity; BioDAO for early stage). A good primer can be found here.

• PBCs/venture philanthropy: Funding for rare disease can be excruciating, so much so that parents are starting biotech companies to find cures for their kids. Two public benefit corporations - Perlara PBC and Rarebase - have sprung up to help fund rare disease research and provide patient advocacy. PBCs can provide returns to shareholders while nonprofits must use any revenue to further the charitable causes, but both can be considered venture philanthropy as they look to tackle societal issues.

• Government: Governmental agencies are becoming more involved in translating promising medicines. At the local level, for example, the MSCRF will help stem cell scientists from MD-based universities start companies, build manufacturing, and connect them to the larger MD VC arm (TEDCO). More broadly, he NIH is open to licensing its technologies, and subdivisions such as the NIA have put on symposia with J&J to inform startups of funding and collaboration opportunities. This is on top of any new initiatives looking to fund/pay existing companies.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week (focus on blood/plasma predictors)

Sci Transl Med: Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life (link)

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.

Commun Biol: Age-related changes in circadian regulation of the human plasma lipidome (link)

Aging alters the amplitude and phase of centrally regulated circadian rhythms. Here we evaluate whether peripheral circadian rhythmicity in the plasma lipidome is altered by aging through retrospective lipidomics analysis on plasma samples collected in 24 healthy individuals (9 females; mean ± SD age: 40.9 ± 18.2 years) including 12 younger (4 females, 23.5 ± 3.9 years) and 12 middle-aged older, (5 females, 58.3 ± 4.2 years) individuals every 3 h throughout a 27-h constant routine (CR) protocol, which allows separating evoked changes from endogenously generated oscillations in physiology. Cosinor regression shows circadian rhythmicity in 25% of lipids in both groups. On average, the older group has a ~14% lower amplitude and a ~2.1 h earlier acrophase of the lipid circadian rhythms (both, p ≤ 0.001). Additionally, more rhythmic circadian lipids have a significant linear component in addition to the sinusoidal across the 27-h CR in the older group (44/56) compared to the younger group (18/58, p < 0.0001). Results from individual-level data are consistent with group-average results. Results indicate that prevalence of endogenous circadian rhythms of the human plasma lipidome is preserved with healthy aging into middle-age, but significant changes in rhythmicity include a reduction in amplitude, earlier acrophase, and an altered temporal relationship between central and lipid rhythms.

J Gerontol A Biol Sci Med Sci: Association of a blood-based aging biomarker index with death and chronic disease: Cardiovascular Health Study (link)

Background: A goal of gerontology is to discover phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that are strongly associated with mortality could be used to define such a phenotype. However, the relation of such an index with multiple chronic conditions warrants further exploration.

Methods: A Biomarker Index (BI) was constructed in the Cardiovascular Health Study (N=3197), with a mean age of 74 years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, interleukin-6, amino-terminal pro-B-type natriuretic peptide, cystatin-C, C-reactive protein, tumor necrosis factor-alpha soluble receptor 1, fasting insulin, and fasting glucose, and was built based on their relationships with mortality. Cox proportional hazards models predicting a composite of death and chronic disease involving cardiovascular disease, dementia, and cancer were calculated with 6 years of follow-up.

Results: The hazard ratio (HR, 95% CI) for the composite outcome of death or chronic disease per category of BI was 1.65 (1.52, 1.80) and 1.75 (1.58, 1.94) in women and men, respectively. The HR (95% CI) per 5 years of age was 1.57 (1.48, 1.67) and 1.55 (1.44, 1.67) in women and men, respectively. Moreover, BI could attenuate the effect of age on the composite outcome by 16.7% and 22.0% in women and men, respectively.

Conclusions: BI was significantly and independently associated with a composite outcome of death and chronic disease, and attenuated the effect of age. The BI that is composed of plasma biomarkers may be a practical intermediate phenotype for interventions aiming to modify the course of aging.

Stem cells / RegenMed

• Sci Adv: Nanoengineered mesenchymal stem cell therapy for pulmonary fibrosis in young and aged mice (link)

• JCI Insight: Circadian regulation of lung repair and regeneration (link)

• Life Sci: Immunomodulatory potential of human clonal mesenchymal stem cells and their extracellular vesicle subpopulations in an inflammatory-mediated diabetic Rhesus monkey model (link)

• BMC Musculoskelet Disord: Expression of proinflammatory cytokines and proinsulin by bone marrow-derived cells for fracture healing in long-term diabetic mice (link)

• Diabetologia: Reversal of dual epigenetic repression of non-canonical Wnt-5a normalises diabetic corneal epithelial wound healing and stem cells (link)

• Wound Repair Regen: Treatment of Aged Wound Healing Models with FGF2 and ABT-737 Reduces the Senescent Cell Population and Increases Wound Closure Rate (link)

• Stem Cell Rev Rep: Activation of MG53 Enhances Cell Survival and Engraftment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Injured Hearts (link)

• Biomater Res: Transplantation of adipose tissue-derived microvascular fragments promotes therapy of critical limb ischemia (link)

• Reviews:

  • Stem Cells Transl Med: Progress In Stem Cells Based Replacement Therapy for Retinal Pigment Epithelium: In Vitro Differentiation to In Vivo Delivery (link)

  • Cell Tissue Res: Influence of type 2 diabetes and obesity on adipose mesenchymal stem/stromal cell immunoregulation (link)

Aging / Longevity

• Translational:

  • Mol Psychiatry: Poorer aging trajectories are associated with elevated serotonin synthesis capacity (link)

  • Life Sci: Baicalein mitigates oxidative stress and enhances lifespan through modulation of Wnt ligands and GATA factor: ELT-3 in Caenorhabditis elegans (link)

• Organ- and disease-specific:

  • Nat Biotechnol: Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain (link)

  • Geroscience: Targeting mitochondria in the aged cerebral vasculature with SS-31, a proteomic study of brain microvessels (link)

  • Nat Commun: Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis (link)

  • Nat Commun: Clearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1 (link)

  • Nat Commun: Multi-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1 (link)

  • Schizophr Bull: Retinal Neurodegeneration as a Potential Biomarker of Accelerated Aging in Schizophrenia Spectrum Disorders (link)

• Other:

  • Nat Med: The Aging Biomarker Consortium represents a new era for aging research in China (link)

• Reviews:

  • Aging (Albany NY): Towards disease-oriented dosing of rapamycin for longevity: does aging exist or only age-related diseases? (link)

  • Nutr Res Rev: Scientific evidence of foods that improve the lifespan and healthspan of different organisms (link)

  • Nat Med: Digital health for aging populations (link)

Model systems / Protocols

• Models:

  • Nat Protoc: Directed differentiation of ureteric bud and collecting duct organoids from human pluripotent stem cells (link)

  • J Mater Chem B: Cardiac organoid: multiple construction approaches and potential applications (link)

• Translational:

  • Sci Rep: Effective SARS-CoV-2 replication of monolayers of intestinal epithelial cells differentiated from human induced pluripotent stem cells (link)

  • Food Chem Toxicol: Model of neural development by differentiating human induced pluripotent stem cells into neural progenitor cells to study the neurodevelopmental toxicity of lead (link)

• Biomaterials:

  • ACS Nano: Living Anisotropic Structural Color Hydrogels for Cardiotoxicity Screening (link)

  • ACS Biomater Sci Eng: Mimicking the Tendon Microenvironment to Enhance Skeletal Muscle Adhesion and Longevity in a Functional Microcantilever Platform (link)

  • Nat Rev Methods Primers: Engineered hydrogels for mechanobiology (link)

  • Pharmacol Res: The application of organ-on-chip models for the prediction of human pharmacokinetic profiles during drug development (link)

Clinical

• Pubs:

  • Lancet Healthy Longev: Brain structure and phenotypic profile of superagers compared with age-matched older adults: a longitudinal analysis from the Vallecas Project (link)

• Newly posted studies:

  • NCT05947175: Vertebral Bone Marrow Clot for Spinal Surgery (link)

  • NCT05947578: The Safety and Tolerability of CLZ-2002 in Patients With Charcot-Marie Tooth Disease (link)

  • NCT05948982: Safety of Umbilical Cord Mesenchymal Stem Cells (UC-MSC) in Patients With Decompensated Hepatitis B Cirrhosis (link)

  • NCT05951777: Autologous Adipose Derived Mesenchymal Stem Cells for Chronic Traumatic Brain Injury (link)

Other (Articles, Perspectives, etc.)

• Nature: The true cost of science’s language barrier for non-native English speakers (link)

• Business:

  • Rutgers: A Generous Gift for the Future of Aging (link)

• Other interesting papers:

  • Immun Ageing: Obesity accelerates age defects in B cells, and weight loss improves B cell function (link)

  • Gut Microbes: Transplantation of gut microbiota from old mice into young healthy mice reduces lean mass but not bone mass (link)

  • Obesity (Silver Spring): Adipocyte hypertrophy in mesenchymal stem cells from infants of mothers with obesity (link)

  • Nature: Organization of the human intestine at single-cell resolution (link)

Astute observers will note these conclusions are not mutually exclusive - indeed, the same paper cited above admitted “…AI chatbots such as ChatGPT-3 can generate a well-differentiated diagnosis list for common chief complaints…” [emphasis mine] but the treatment algorithm can be improved particularly for more severe patient presentations. Overall, this article in JAMA Forum best best encompasses my views around AI in the near term:

1. AI is likely to substitute for rote activities that humans currently perform

2. In clinical care, AI is more likely to complement clinicians than substitute for them

3. Develop AI applications that enhance efficiency by enabling less expensive monitoring, diagnosis, and personnel needs

4. AI algorithms should not just replicate human thinking processes but should aim to exceed them

5. It is important to be clear about what AI is not good at

I’ve included below a few links to interesting perspectives and use cases on AI in healthcare that I’ve read as part of diligence for this post. This is definitely one topic I would love to hear more perspectives on, if anyone has good links to share or would like to chat.

• Nat Rev Neuro: AI-based tools for the diagnosis and treatment of rare neurological disorders (link)

• Lancet Digit Health: Artificial intelligence-based model to classify cardiac functions from chest radiographs: a multi-institutional, retrospective model development and validation study (link)

• JAMA: Marketing and US Food and Drug Administration Clearance of Artificial Intelligence and Machine Learning Enabled Software in and as Medical Devices: A Systematic Review (link)

• JAMA: Generative AI in Health Care and Liability Risks for Physicians and Safety Concerns for Patients (link)

• Goldman: How artificial intelligence is accelerating innovation in healthcare (link)

• Nature: Scientists used ChatGPT to generate an entire paper from scratch — but is it any good? (link)

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

EMBO J: Cellular senescence induction leads to progressive cell death via the INK4a-RB pathway in naked mole-rats (link)

Naked mole-rats (NMRs) have exceptional longevity and are resistant to age-related physiological decline and diseases. Given the role of cellular senescence in aging, we postulated that NMRs possess unidentified species-specific mechanisms to prevent senescent cell accumulation. Here, we show that upon induction of cellular senescence, NMR fibroblasts underwent delayed and progressive cell death that required activation of the INK4a-retinoblastoma protein (RB) pathway (termed "INK4a-RB cell death"), a phenomenon not observed in mouse fibroblasts. Naked mole-rat fibroblasts uniquely accumulated serotonin and were inherently vulnerable to hydrogen peroxide (H2 O2 ). After activation of the INK4a-RB pathway, NMR fibroblasts increased monoamine oxidase levels, leading to serotonin oxidization and H2 O2 production, which resulted in increased intracellular oxidative damage and cell death activation. In the NMR lung, induction of cellular senescence caused delayed, progressive cell death mediated by monoamine oxidase activation, thereby preventing senescent cell accumulation, consistent with in vitro results. The present findings indicate that INK4a-RB cell death likely functions as a natural senolytic mechanism in NMRs, providing an evolutionary rationale for senescent cell removal as a strategy to resist aging.

Nature: Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease (link)

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

Elife: Tracing the history of a heart (link)

Newly developed tools will help researchers understand how the human heart develops and build better models to study and treat congenital heart disease.

Stem cells / RegenMed

• Proc Natl Acad Sci U S A: NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis (link)

• ACS Nano: Cell-Free Osteoarthritis Treatment with Sustained-Release of Chondrocyte-Targeting Exosomes from Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes (link)

• NPJ Regen Med: MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice (link)

• EMBO Rep: Patronin/CAMSAP promotes reactivation and regeneration of Drosophila quiescent neural stem cells (link)

• Hum Gene Ther: Establishment of the effectiveness of early versus late stem cell gene therapy in Mucopolysaccharidosis II for treating central versus peripheral disease (link)

• Cell Commun Signal: ATP purinergic receptor signalling promotes Sca-1+ cell proliferation and migration for vascular remodelling (link)

• NPJ Regen Med: Regeneration of tracheal neotissue in partially decellularized scaffolds (link)

• Biol Res: Hyperbaric oxygen treatment increases intestinal stem cell proliferation through the mTORC1/S6K1 signaling pathway in Mus musculus (link)

• FASEB J: Transplantation of in vitro prefabricated adipose organoids attenuates skin fibrosis by restoring subcutaneous fat and inducing dermal adipogenesis (link)

• Reviews:

  • Acta Obstet Gynecol Scand: Prospects for use of bioengineered tissue from stem cells in gynecology (link)

  • Stem Cell Rev Rep: Current Progress in Stem Cell Therapy for Male Infertility (link)

  • Stem Cells Transl Med: Fulfilling the Promise of RNA Therapies for Cardiac Repair and Regeneration (link)

  • Tissue Eng Part B Rev: Stem cell - based therapies for auditory hair cell regeneration and treatment of hearing loss (link)

Aging / Longevity

• Translational:

  • EMBO J: Large-scale across species transcriptomic analysis identifies genetic selection signatures associated with longevity in mammals (link)

  • Cell Metab: Prolonged fasting times reap greater geroprotective effects when combined with caloric restriction in adult female mice (link)

• Organ- and disease-specific:

  • Circ J: Exploration of New Therapies for Heart Failure Targeting Age-Related Mechanisms (link)

  • Skelet Muscle: Age-related gene expression signatures from limb skeletal muscles and the diaphragm in mice and rats reveal common and species-specific changes (link)

  • J Neuroinflammation: NLRP3-GABA signaling pathway contributes to the pathogenesis of impulsive-like behaviors and cognitive deficits in aged mice (link)

• Other:

  • Aging (Albany NY): Chemically induced reprogramming to reverse cellular aging (link)

  • Aging (Albany NY): Predicting lifespan-extending chemical compounds for C. elegans with machine learning and biologically interpretable features (link)

• Reviews:

  • Geroscience: The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery (link)

  • Aging Cell: NAD metabolism: Role in senescence regulation and aging (link)

  • Cerebellum: Consensus Paper: Cerebellum and Ageing (link)

  • Annu Rev Neurosci: Cholesterol Metabolism in Aging and Age-Related Disorders (link)

Model systems / Protocols

• Models:

  • Eur J Immunol: Enhanced in vitro type 1 conventional dendritic cell generation via the recruitment of hematopoietic stem cells and early progenitors by Kit ligand (link)

  • Inflamm Regen: Effect of aging on the formation and growth of colonic epithelial organoids by changes in cell cycle arrest through TGF-β-Smad3 signaling (link)

  • Biotechnol Bioeng: Early dynamic changes in iPSC oxygen consumption rate predict future cardiomyocyte differentiation (link)

  • Expert Opin Drug Discov: 3D bioprinting for organ and organoid models and disease modeling (link)

• Translational:

  • Sci Adv: An organoid-based CRISPR-Cas9 screen for regulators of intestinal epithelial maturation and cell fate (link)

  • Curr Opin Pharmacol: Targeting cAMP signaling compartments in iPSC-derived models of cardiovascular disease (link)

• Biomaterials:

  • Adv Sci (Weinh): 3D Printing of Microenvironment-Specific Bioinspired and Exosome-Reinforced Hydrogel Scaffolds for Efficient Cartilage and Subchondral Bone Regeneration (link)

  • Adv Mater: Polyhedron-Like Biomaterials for Innervated and Vascularized Bone Regeneration (link)

  • ACS Nano: A Redox Homeostasis Modulatory Hydrogel with GLRX3+ Extracellular Vesicles Attenuates Disc Degeneration by Suppressing Nucleus Pulposus Cell Senescence (link)

  • J Mater Chem B: Strontium-doped mesoporous bioglass nanoparticles for enhanced wound healing with rapid vascularization (link)

  • ACS Appl Bio Mater: Human Adipose-Derived Mesenchymal Stem Cell-Secreted Extracellular Matrix Coating on a Woven Nanotextile Vascular Patch for Improved Endothelial Cell Response (link)

Clinical

• Pubs:

  • ESC Heart Fail: Causality between heart failure and epigenetic age: a bidirectional Mendelian randomization study (link)

  • J Gerontol A Biol Sci Med Sci: The protective effect of familial longevity persists after age 100: Findings from the Danish national registers (link)

  • J Gerontol A Biol Sci Med Sci: Polygenic propensity for longevity, APOE-ε4 status, dementia diagnosis and risk for cause-specific mortality: a large population-based longitudinal study of older adults (link)

  • Nurs Open: Impact of caregivers' psychological and caregiving status on recruitment, conversion, and retention in stem cell therapy trials for cerebral palsy: A prospective survey analysis (link)

• Corporate:

  • Cresilon: Cresilon Receives First FDA Clearance For Human Use of Hemostatic Gel Technology (link)

• Newly posted studies:

  • NCT05940610: The Safety and Efficacy of MSC-EVs in Acute/Acute-on-Chronic Liver Failure (link)

  • NCT05939778: A Study of TH-SC01 in the Treatment of Radiation-induced Rectal Injury (link)

  • NCT05939167: Mesenchymal Stem Cells Treatment for AIDS Patients at Late Stage (link)

  • NCT05944627: Evaluate Safety and Explore Efficacy of FURESTEM-OA Kit Inj. in Patients With Knee Osteoarthritis (link)

  • NCT05941234: Stem Cell Analysis, Omics (Including Immunomics) and Artificial Intelligence in Glioblastoma (IPerGlioGEM) (link)

Other (Articles, Perspectives, etc.)

• Business:

  • Endpoints: Tenpoint Therapeutics launches with $70M to restore vision with stem cell therapies and ‘reprogramming’ medicines (link)

  • Bloomberg: Coloplast Buys Fish-Skin Tissue Graft Maker for $1.3 Billion (link)

  • WSJ: The Longevity Clinic Will See You Now—for $100,000 (link)

  • Nat Rev Drug Discov: FDA new drug approvals in Q2 2023 (link)

  • JAMA Health Forum: Drug Development-Social and Private Returns (link)

• Other interesting papers:

  • Nat Biotechnol: Whole-body cellular mapping in mouse using standard IgG antibodies (link)

  • Adv Healthc Mater: Artificial Neural Processing-Driven Bioelectronic Nose for The Diagnosis of Diabetes And Its Complications (link)

  • BMC Geriatr: Association of cardiovascular health at old age with all-cause mortality: a prospective cohort study in China (link)

Earlier this year data from >141k UK Biobank samples showed a maltreatment number-dependent effect on telomere length, i.e. the more types of maltreatment the shorter the telomeres, even when adjusting for confounding factors; shorter telomeres in these patients were associated with diagnoses of depression and PTSD. This data expands on previous work (here) showing maltreatment (physical neglect) led to shorter telomeres and was predictive of depression, but depression itself was not predictive of shorter telomeres. Interestingly, one study showed neglect was the only form of maltreatment to have longitudinal impact on epigenomic readings (here), which may point to physical neglect being more responsible for poor long-term physical and mental health outcomes, including shorter lifespan.

Researchers in this realm have the Herculean and unenviable task of controlling for myriad aberrant variables, which of course can only go so far. Other researchers have sought deeper explanations for poor long-term health and shortened longevity in those having experienced maltreatment: for example, negative sociological pressures tied to biological effects of maltreatment (here, early menses and rapid aging); or cellular mechanism exhaustion leading to shorter telomeres and lifespan following maltreatment (here, pleiotropic roles of the shelterin protein).

It goes without saying that early life adversity is truly terrible for reasons beyond just biology. For those of us thinking about how to help these patients (and many others), it may be important to consider how early life may impact a disease state decades later. While we will not be asking the half of Americans with heart disease whether they had early life trauma, a 38yo presenting with CRP >10mg/L may benefit from a quick get-to-know-you question about their early life.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

*Programming note: RegenMed Journal Club will be off next week, back July 17th. Have a Happy Fourth everyone!

Top papers of the week (focus on calorie restriction and aging)

Cell Rep: Dietary restriction mitigates the age-associated decline in mouse B cell receptor repertoire diversity (link)

Aging impairs the capacity to respond to novel antigens, reducing immune protection against pathogens and vaccine efficacy. Dietary restriction (DR) extends life- and health span in diverse animals. However, little is known about the capacity of DR to combat the decline in immune function. Here, we study the changes in B cell receptor (BCR) repertoire during aging in DR and control mice. By sequencing the variable region of the BCR heavy chain in the spleen, we show that DR preserves diversity and attenuates the increase in clonal expansions throughout aging. Remarkably, mice starting DR in mid-life have repertoire diversity and clonal expansion rates indistinguishable from chronic DR mice. In contrast, in the intestine, these traits are unaffected by either age or DR. Reduced within-individual B cell repertoire diversity and increased clonal expansions are correlated with higher morbidity, suggesting a potential contribution of B cell repertoire dynamics to health during aging.

Geroscience: Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension (link)

Calorie restriction (CR) can prolong human lifespan, but enforcing long-term CR is difficult. Thus, a drug that reproduces the effects of CR without CR is required. More than 10 drugs have been listed as CR mimetics (CRM), and some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, whereas the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Intriguingly, recent reports have revealed the beneficial effects of CRMs on the body such as improving the host body condition via intestinal bacteria and their metabolites. This beneficial effect of gut microbiota may lead to lifespan extension. Thus, CRMs may have a dual effect on longevity. However, no reports have collectively discussed them as CRMs; hence, our knowledge about CRM and its physiological effects on the host remains fragmentary. This study is the first to present and collectively discuss the accumulative evidence of CRMs improving the gut environments for healthy lifespan extension, after enumerating the latest scientific findings related to the gut microbiome and CR. The conclusion drawn from this discussion is that CRM may partially extend the lifespan through its effect on the gut microbiota. CRMs increase beneficial bacteria abundance by decreasing harmful bacteria rather than increasing the diversity of the microbiome. Thus, the effect of CRMs on the gut could be different from that of conventional prebiotics and seemed similar to that of next-generation prebiotics.

PLoS One: Endocytic coelomocytes are required for lifespan extension by axenic dietary restriction (link)

A rather peculiar but very potent means of achieving longevity is through axenic dietary restriction (ADR), where animals feed on (semi-)defined culture medium in absence of any other lifeform. The little knowledge we already have on ADR is mainly derived from studies using the model organism Caenorhabditis elegans, where ADR more than doubles organismal lifespan. What is underlying this extreme longevity so far remains enigmatic, as ADR seems distinct from other forms of DR and bypasses well-known longevity factors. We here focus first on CUP-4, a protein present in the coelomocytes, which are endocytic cells with a presumed immune function. Our results show that loss of cup-4 or of the coelomocytes affects ADR-mediated longevity to a similar extent. As the coelomocytes have been suggested to have an immune function, we then investigated different central players of innate immune signalling, but could prove no causal links with axenic lifespan extension. We propose that future research focuses further on the role of the coelomocytes in endocytosis and recycling in the context of longevity.

Stem cells / RegenMed

• Sci Rep: In major joint diseases the human synovium retains its potential to form repair cartilage (link)

• Stem Cell Res Ther: Mesenchymal progenitor cells from non-inflamed versus inflamed synovium post-ACL injury present with distinct phenotypes and cartilage regeneration capacity (link)

• Biotechnol J: Cyclic mechanical stretch pre-stimulated bone marrow mesenchymal stem cells promote the healing of infected bone defect in a mouse model (link)

• Stem Cell Res Ther: Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice (link)

• Blood Adv: Mesenchymal Stem Cells ameliorate Chronic GVHD by Boosting Thymic Regeneration in a CCR9-dependent manner in mice (link)

• Aging (Albany NY): iPSC-derived exosomes promote angiogenesis in naturally aged mice (link)

• Sci Rep: Remodeled eX vivo muscle engineered tissue improves heart function after chronic myocardial ischemia (link)

• Stem Cell Res Ther: GABAergic neurons differentiated from BDNF- and Dlx2-modified neural stem cells restore disrupted neural circuits in brainstem stroke (link)

• CNS Neurosci Ther: Therapeutic role of mesenchymal stem cell-derived extracellular vesicles in neuroinflammation and cognitive dysfunctions induced by binge-like ethanol treatment in adolescent mice (link)

• Sci Transl Med: Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice (link)

• Stem Cells: Artificial intelligence supports automated characterization of differentiated human pluripotent stem cells (link)

• Reviews:

  • Stem Cell Res Ther: Dysregulation of histone modifications in bone marrow mesenchymal stem cells during skeletal ageing: roles and therapeutic prospects (link)

  • Cell Tissue Bank: The role of oxygen tension in cell fate and regenerative medicine: implications of hypoxia/hyperoxia and free radicals (link)

  • Clin Liver Dis: Liver Regeneration in Acute on Chronic Liver Failure (link)

Aging / Longevity

• Translational:

  • Aging Clin Exp Res: Association between serum soluble α-klotho and bone mineral density (BMD) in middle-aged and older adults in the United States: a population-based cross-sectional study (link)

  • Aging (Albany NY): A novel peptide 'T14' reflects age and photo-aging in human skin (link)

  • Aging (Albany NY): Identification and validation of a 7-genes prognostic signature for adult acute myeloid leukemia based on aging-related genes (link)

  • Nat Hum Behav: Mendelian randomization evidence for the causal effects of socio-economic inequality on human longevity among Europeans (link)

• Organ- and disease-specific:

  • Eur Heart J: Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice (link)

  • Protein Cell: A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes (link)

• Other:

  • Sci Adv: Human PBMC scRNA-seq-based aging clocks reveal ribosome to inflammation balance as a single-cell aging hallmark and super longevity (link)

• Reviews:

  • Nat Aging: The meaning of adaptation in aging: insights from cellular senescence, epigenetic clocks and stem cell alterations (link)

  • Nat Aging: Considerations for reproducible omics in aging research (link)

  • Endocr Rev: Nicotinamide Adenine Dinucleotide in Aging Biology: Potential Applications and Many Unknowns (link)

Model systems / Protocols

• Models:

  • Mol Psychiatry: 3D bioengineered neural tissue generated from patient-derived iPSCs mimics time-dependent phenotypes and transcriptional features of Alzheimer's disease (link)

  • Nature: A model of the post-implantation human embryo derived from pluripotent stem cells (link)

  • Nature: Self-patterning of human stem cells into post-implantation lineages (link)

  • Development: SIX1+PAX3+ identify a progenitor for myogenic lineage commitment from hPSCs (link)

  • Lab Anim (NY): Generation of the NeoThy mouse model for human immune system studies (link)

• Translational:

  • Proc Natl Acad Sci U S A: Functional calcium-responsive parathyroid glands generated using single-step blastocyst complementation (link)

  • Sci Rep: Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics (link)

• Biomaterials:

  • ACS Appl Mater Interfaces: Nanoscale β-TCP-Laden GelMA/PCL Composite Membrane for Guided Bone Regeneration (link)

  • Adv Healthc Mater: Convergence of Calcium Channel Regulation and Mechanotransduction in Skeletal Regenerative Biomaterial Design (link)

  • Otolaryngol Head Neck Surg: Long-Term Chondrocyte Retention in Partially Decellularized Tracheal Grafts (link)

Clinical

• Clinical:

  • J Cosmet Dermatol: Clinical effect of stem cell transplantation combined with 308-nm excimer laser therapy for 56 cases of vitiligo (link)

  • J Cosmet Dermatol: Efficacy of combined treatment with human adipose tissue stem cell-derived exosome-containing solution and microneedling for facial skin aging: A 12-week prospective, randomized, split-face study (link)

  • Clin Exp Rheumatol: Autologous fat or adipose-derived stem cells grafting in systemic sclerosis treatment: a systematic review and meta-analysis (link)

  • Stem Cell Res Ther: Allogenic mesenchymal stromal cells and their extracellular vesicles in COVID-19 induced ARDS: a randomized controlled trial (link)

• Corporate:

  • Sernova: Sernova Announces Positive Updated Interim Phase 1/2 Clinical Data for the Cell Pouch System™ at American Diabetes Association 83rd Scientific Sessions (link)

  • Bayer: BlueRock’s neuronal stem cell therapy for Parkinson’s disease is first to show positive results in Phase I clinical study (link)

• Newly posted studies:

  • NCT05921058: The Effects of Mesenchymal Stem Cell Secretome in Lupus Patients (link)

  • NCT05925036: Novel Cellular Therapy for the Treatment of Pain Associated With Chronic Pancreatitis (MSCPainRelief) (link)

  • NCT05925608: Clinical Trial of Human Allogenic Culture-expanded Bone Marrow-derived Mesenchymal Stem Cells (CardiALLO) (link)

  • NCT05924373: Human Dental Pulp Mesenchymal Stem Cells for the Treatment of Chronic Periodontitis Patients (link)

  • NCT05925647: The Effects of Mesenchymal Stem Cell Secretome in Rheumatoid Arthritis Patients (link)

Other (Articles, Perspectives, etc.)

• FT: Biotech begins human trials of drug designed by artificial intelligence (link)

• Business:

  • FDA: FDA Approves First Cellular Therapy to Treat Patients with Type 1 Diabetes (link)

  • Eli Lilly: Lilly to Acquire Sigilon Therapeutics (link)

  • Nat Biotechnol: Defining a longevity biotechnology company (link)

• Other interesting papers:

  • J Health Soc Behav: "I Love You to Death": Social Networks and the Widowhood Effect on Mortality (link)

  • Adv Sci (Weinh): Efficient Mining of Anticancer Peptides from Gut Metagenome (link)

  • Nature: Reprogramming tumour-associated macrophages to outcompete cancer cells (link)

Certain techniques, such as bioprinting, are likely to benefit from microgravity due to interactions between the printing machinery and biological material (a nice review focused on cardiac tissue can be found here). And companies are receiving funding or partnerships to advance biological space tech (Pluristem and NASA; 3D Bioprinting Solutions and the ISS; and your requisite consultancy telling you how to get it all done). Still, even NASA has shown microgravity has detrimental effects on multiple regenerative processes, such as bone, with further work planned for human neural stem cells and oligodendrocytes.

These are fascinating projects and I am intrigued, but remain highly skeptical of any benefits that overcome the expense of transport, long-term cell viability, and significant delta vs current land-based techniques. If anyone has any informative reading on the subject I would love to take a look!

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Cell Stem Cell: Advanced human iPSC-based preclinical model for Parkinson's disease with optogenetic alpha-synuclein aggregation (link)

Human induced pluripotent stem cells (hiPSCs) offer advantages for disease modeling and drug discovery. However, recreating innate cellular pathologies, particularly in late-onset neurodegenerative diseases with accumulated protein aggregates including Parkinson's disease (PD), has been challenging. To overcome this barrier, we developed an optogenetics-assisted α-synuclein (α-syn) aggregation induction system (OASIS) that rapidly induces α-syn aggregates and toxicity in PD hiPSC-midbrain dopaminergic neurons and midbrain organoids. Our OASIS-based primary compound screening with SH-SY5Y cells identified 5 candidates that were secondarily validated with OASIS PD hiPSC-midbrain dopaminergic neurons and midbrain organoids, leading us to finally select BAG956. Furthermore, BAG956 significantly reverses characteristic PD phenotypes in α-syn preformed fibril models in vitro and in vivo by promoting autophagic clearance of pathological α-syn aggregates. Following the FDA Modernization Act 2.0's emphasis on alternative non-animal testing methods, our OASIS can serve as an animal-free preclinical test model (newly termed "nonclinical test") for the synucleinopathy drug development.

Aging Cell: Deletion of enzymes for de novo NAD+ biosynthesis accelerated ovarian aging (link)

Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD+ ) in ovarian aging. However, the roles of de novo NAD+ biosynthesis on ovarian aging are still unknown. Here, we found that genetic ablation of Ido1 (indoleamine-2,3-dioxygenase 1) or Qprt (Quinolinate phosphoribosyl transferase), two critical genes in de novo NAD+ biosynthesis, resulted in decreased ovarian NAD+ levels in middle-aged mice, leading to subfertility, irregular estrous cycles, reduced ovarian reserve, and accelerated aging. Moreover, we observed impaired oocyte quality, characterized by increased reactive oxygen species and spindle anomalies, which ultimately led to reduced fertilization ability and impaired early embryonic development. A transcriptomic analysis of ovaries in both mutant and wild-type mice revealed alterations in gene expression related to mitochondrial metabolism. Our findings were further supported by the observation of impaired mitochondrial distribution and decreased mitochondrial membrane potential in the oocytes of knockout mice. Supplementation with nicotinamide riboside (NR), an NAD+ booster, in mutant mice increased ovarian reserve and improved oocyte quality. Our study highlights the importance of the NAD+ de novo pathway in middle-aged female fertility.

Regen Med: Comparative analysis of rule elements for transportation of cell therapy products among regulations and standards (link)

Aim: This study aimed to identify the elements involved in the transportation of cell therapy products by conducting a comparative analysis of four related international standards for temperature-controlled delivery and good distribution practice (GDP). Methods: An analytical framework was constructed to cover the entire transportation process. The descriptions of each element in the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) GDP, International Organization for Standardization (ISO) 21973, Foundation for the Accreditation of Cellular Therapy Common Standards for Cellular Therapies and ISO 23412 were compared. Results: The study identified some elements that were present in the PIC/S GDP and other standards but were absent in ISO 21973, and vice versa. These elements are crucial in view of the increasing opportunities to transport allogeneic cells in the future. Conclusion: The study identified the necessary elements that should be included in the development of transport regulations for cell therapy products.

Stem cells / RegenMed

• Ann Surg: Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs (link)

• Sci Rep: Transcriptomic and in vivo approaches introduced human iPSC-derived microvesicles for skin rejuvenation (link)

• J Clin Invest: Ruxolitinib improves hematopoietic regeneration by restoring mesenchymal stromal cell function in acute graft-versus-host disease (link)

• Inflamm Regen: Enhancement of bone regeneration by coadministration of angiogenic and osteogenic factors using messenger RNA (link)

• BMC Med: Detrimental alteration of mesenchymal stem cells by an articular inflammatory microenvironment results in deterioration of osteoarthritis (link)

• Stem Cells Dev: Human Induced Hepatocytes-Derived Extracellular Vesicles Ameliorated Liver Fibrosis in Mice via Suppression of TGF-β1/Smad Signaling and Activation of Nrf2/HO-1 Signaling (link)

• Stem Cell Res Ther: Comparison of the therapeutic effects between stem cells and exosomes in primary ovarian insufficiency: as promising as cells but different persistency and dosage (link)

• Proc Natl Acad Sci U S A: Single-cell transcriptomics reveals maturation of transplanted stem cell-derived retinal pigment epithelial cells toward native state (link)

• Nat Commun: Intracellular pH dynamics regulates intestinal stem cell lineage specification (link)

• Reviews:

o Expert Opin Biol Ther: Culturing human pluripotent stem cells for regenerative medicine (link)

o Immunotherapy: Cancer immunotherapy via stem cell-derived NK cells (link)

o Stem Cell Res Ther: Gene editing with 'pencil' rather than 'scissors' in human pluripotent stem cells (link)

o J Cell Physiol: The origin, progress, and application of cell-based cardiac regeneration therapy (link)

Aging / Longevity

• Translational:

o Aging Cell: Releasing YAP dysfunction-caused replicative toxicity rejuvenates mesenchymal stem cells (link)

• Organ- and disease-specific:

o Nat Neurosci: Multicellular communities are perturbed in the aging human brain and Alzheimer's disease (link)

o Acta Neuropathol Commun: Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy (link)

o Research (Wash D C): Protein Arginine Methyltransferase 1 Ablation in Motor Neurons Causes Mitochondrial Dysfunction Leading to Age-related Motor Neuron Degeneration with Muscle Loss (link)

o Elife: Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons (link)

o Aging Cell: The role of aging and brain-derived neurotrophic factor signaling in expression of base excision repair genes in the human brain (link)

o Commun Biol: Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype (link)

o Nature: Signalling by senescent melanocytes hyperactivates hair growth (link)

o Eur Heart J: Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study (link)

• Other:

o Aging (Albany NY): Age prediction from human blood plasma using proteomic and small RNA data: a comparative analysis (link)

• Reviews:

o Am J Physiol Cell Physiol: The life and times of cellular senescence in skeletal muscle: friend or foe for homeostasis and adaptation? (link)

Model systems / Protocols

• Models:

o Stem Cell Rev Rep: Reprogramming Human Female Adipose Mesenchymal Stem Cells into Primordial Germ Cell-Like Cells (link)

o Adv Healthc Mater: Supramolecular Assemblies of Glycopeptides Enhance Gap Junction Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes via Inducing Spheroids Formation to Optimize Cardiac Repair (link)

o Protein Cell: Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids (link)

o Glia: Integrating human iPSC-derived macrophage progenitors into retinal organoids to generate a mature retinal microglial niche (link)

o Nat Commun: The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson's disease (link)

o Transl Psychiatry: Human pluripotent stem cell (hPSC) and organoid models of autism: opportunities and limitations (link)

• Biomaterials:

o Biomater Sci: Functionalized hydrogel-microsphere composites stimulating neurite outgrowth for vascularized bone regeneration (link)

o Adv Healthc Mater: Surface Functional Modification by Ti3 C2 Tx MXene on Plla Nanofibers for Optimizing Neural Stem Cell Engineering (link)

o Adv Mater: Adipose Mesenchymal Stem Cell-Derived Exosomes Promote Keratinocytes And Fibroblasts Embedded in Collagen/Platelet-Rich Plasma Scaffold And Accelerate Wound Healing (link)

o Am J Sports Med: Bioactive Scaffold With Spatially Embedded Growth Factors Promotes Bone-to-Tendon Interface Healing of Chronic Rotator Cuff Tear in Rabbit Model (link)

Clinical

• J Cosmet Dermatol: Vacuum and electromagnetic field in synergy for skin rejuvenation: A retrospective study on 217 patients (link)

• J Extracell Vesicles: First-in-human clinical trial of allogeneic, platelet-derived extracellular vesicles as a potential therapeutic for delayed wound healing (link)

• Am J Sports Med: Clinical Efficacy and Safety of the Intra-articular Injection of Autologous Adipose-Derived Mesenchymal Stem Cells for Knee Osteoarthritis: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial (link)

• Plast Reconstr Surg: A clinical trial of treating androgenic alopecia with mesenchymal stem cell suspension derived from autologous hair follicle (link)

• Aesthetic Plast Surg: Stem Cell Enriched Fat Grafts versus Autologous Fat Grafts in Reconstructive Surgery: Systematic Review and Meta-Analysis (link)

• Int J Ophthalmol: Assessment of the effects of intrastromal injection of adipose-derived stem cells in keratoconus patients (link)

• Newly posted studies:

o NCT05909488: Role of UC-MSC and CM to Inhibit Vision Loss in Retinitis Pigmentosa Phase II/III (link)

o NCT05909735: Treatment of LSCD With DM (link)

Other (Articles, Perspectives, etc.)

• WSJ: Chicken Grown From Cells Heads to U.S. Dinner Tables (link)

• Science: Biologists create detailed lab replicas of early human embryos (link)

• Business:

o Vertex: Vertex Presents Positive VX-880 Results From Ongoing Phase 1/2 Study in Type 1 Diabetes at the American Diabetes Association 83rd Scientific Sessions (link)

o Regen Med: Industry updates from the field of stem cell research and regenerative medicine in May 2023 (link)

• Other interesting papers:

o Nat Commun: Leveraging football accelerometer data to quantify associations between repetitive head impacts and chronic traumatic encephalopathy in males (link)

o BMC Med: Trajectories of cardiac troponin in the decades before cardiovascular death: a longitudinal cohort study (link)

o JAMA Intern Med: Comparison of Medical and Mental Health Sequelae Following Hospitalization for COVID-19, Influenza, and Sepsis (link)

Dr. Knoeplfer goes a step beyond by asking how many injections patients generally receive(d), with “one” (56%) being the most common and “five” or “six to ten” being the least common at 0.0%. This is an important consideration as “the total cost of stem cell ‘therapy’ is the product of the cost per injection times the # of injections” and “[unproven stem cell clinics] also often encourage patients to get many injections”. This line of evidence tracks together, since single injections often run $2.5-5k and people most often get few injections (1-4, >90% of respondents), which is why total expenditure commonly runs $2.5-20k.

Unfortunately, insurance does not usually cover unproven stem cell treatments, and the evidence for the use of many unapproved therapies is lacking (i.e., cerebral palsy) and contradictory (stroke: positive and negative). I am a huge proponent of increasing the number of rigorous stem cell trials to help benefit patients, but it is a shame that some individuals are getting fleeced and/or seriously injured at these clinics. Hopefully some of the currently active 376 stem cell trials produce something transformative!

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week (focus on stem cell trials)

Stem Cell Res Ther: Cartilage regeneration and inflammation modulation in knee osteoarthritis following injection of allogeneic adipose-derived mesenchymal stromal cells: a phase II, triple-blinded, placebo controlled, randomized trial (link)

Background: Intra-articular injection of mesenchymal stromal cells (MSCs) with immunomodulatory features and their paracrine secretion of regenerative factors proposed a noninvasive therapeutic modality for cartilage regeneration in knee osteoarthritis (KOA).

Methods: Total number of 40 patients with KOA enrolled in two groups. Twenty patients received intra-articular injection of 100 × 10⁶ allogeneic adipose-derived mesenchymal stromal cells (AD-MSCs), and 20 patients as control group received placebo (normal saline). Questionnaire-based measurements, certain serum biomarkers, and some cell surface markers were evaluated for 1 year. Magnetic resonance imaging (MRI) before and 1 year after injection was performed to measure possible changes in the articular cartilage.

Results: Forty patients allocated including 4 men (10%) and 36 women (90%) with average age of 56.1 ± 7.2 years in control group and 52.8 ± 7.5 years in AD-MSCs group. Four patients (two patients from AD-MSCs group and two patients from the control group) excluded during the study. Clinical outcome measures showed improvement in AD-MSCs group. Hyaluronic acid and cartilage oligomeric matrix protein levels in blood serum decreased significantly in patients who received AD-MSCs (P < 0.05). Although IL-10 level significantly increased after 1 week (P < 0.05), the serum level of inflammatory markers dramatically decreased after 3 months (P < 0.001). Expressions of CD3, CD4, and CD8 have a decreasing trend during 6-month follow-up (P < 0.05), (P < 0.001), and (P < 0.001), respectively. However, the number of CD25⁺ cells increased remarkably in the treatment group 3 months after intervention (P < 0.005). MRI findings showed a slight increase in the thickness of tibial and femoral articular cartilages in AD-MSCs group. The changes were significant in the medial posterior and medial anterior areas of ​​the tibia with P < 0.01 and P < 0.05, respectively.

Conclusion: Inter-articular injection of AD-MSCs in patients with KOA is safe. Laboratory data, MRI findings, and clinical examination of patients at different time points showed notable articular cartilage regeneration and significant improvement in the treatment group.

BMC Musculoskelet Disord: Repeated intra-articular injections of umbilical cord-derived mesenchymal stem cells for knee osteoarthritis: a phase I, single-arm study (link)

Introduction: Stem cell therapy has emerged as an effective treatment for multiple diseases, and some studies also demonstrate that it may be a promising treatment for osteoarthritis (OA). However, few studies have clarified the safety of repeated intra-articular injection of human umbilical cord-derived mesenchymal stem cells (UC-MSCs). To promote its application in treating OA, we conducted an open-label trial to investigate the safety of repeated intra-articular injections of UC-MSCs.

Methods: Fourteen patients with OA (Kellgrene-Lawrence grade 2 or 3) who received repeated intra-articular injections of UC-MSCs were evaluated in three months of follow-up. The primary outcomes were the adverse events, and the second outcomes included visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores and SF-12 quality of life score.

Results: A total of 5 of 14 patients (35.7%) experienced transient adverse reactions, which resolved spontaneously. All patients showed some improvement in knee function limitation and pain after receiving stem cell therapy. VAS score 6.0 to 3.5, WOMAC score 26.0 to 8.5, MOCART score 42.0 to 58.0, SF-12 score 39.0 to 46.0.

Conclusion: Repeated intra-articular injection of UC-MSCs demonstrates safety in treating OA and does not induce serious adverse events. This treatment may transiently improve symptoms in patients with knee OA and may be a potential therapeutic option for OA.

Blood Adv: Donor Bone Marrow Derived Macrophage Engraftment into the Central Nervous System of Allogeneic Transplant Patients (link)

Hematopoietic stem cell transplantation is a well-known treatment of hematologic malignancies wherein nascent stem cells provide a regenerating marrow and immunotherapy against the tumor. The progeny of hematopoietic stem cells also populate a wide spectrum of tissues, including the brain, as bone marrow derived macrophages similar to microglial cells. We developed a sensitive and novel combined IHC and XY FISH assay to detect, quantify and characterize donor cells in the cerebral cortex of 19 female allogeneic stem cell transplant patients. We show that the number of male donor cells ranged from 0.14-3.0% of total cells or 1.2-25% of microglial cells. Using tyramide based fluorescent IHC we found at least 80% of the donor cells express the microglial marker IBA1 consistent with being bone marrow derived macrophages. The percentage of donor cells was related to pretransplant conditioning; donor cells from radiation based myeloablative cases averaged 8.1% of microglial cells, while those from non-myeloablative cases averaged only 1.3%. The number of donor cells in patients conditioned with Busulfan or Treosulfan based myeloablation were similar to TBI based conditioning; donor cells averaged 6.8% of microglial cells. Notably, patients who received multiple transplants and those with the longest post-transplant survival had the highest level of donor engraftment, with donor cells averaging 16.3% of microglial cells. Our work represents the largest study characterizing bone marrow-derived macrophages in post-transplant patients. The efficiency of engraftment observed in our study warrants future research on microglial replacement as a therapeutic option for disorders of the central nervous system.

Stem cells / RegenMed

• Stem Cell Res Ther: Identification of mesenchymal-to-epithelial transition during heart regeneration through genetic lineage tracing (link)

• Development: The translation initiation factor homolog eif4e1c regulates cardiomyocyte metabolism and proliferation during heart regeneration (link)

• Nat Biomed Eng: Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei (link)

• Stem Cell Res Ther: Bioactivity of human adult stem cells and functional relevance of stem cell-derived extracellular matrix in chondrogenesis (link)

• Aging (Albany NY): Machine learning and single cell RNA sequencing analysis identifies regeneration-related hepatocytes and highlights a Birc5-related model for identifying cell proliferative ability (link)

• Clin Transl Med: Human mesenchymal stem-derived extracellular vesicles improve body growth and motor function following severe spinal cord injury in rat (link)

Aging / Longevity

• Organ- and disease-specific

  • Stem Cell Reports: Aging disrupts gene expression timing during muscle regeneration (link)

  • Aging (Albany NY): Identification of novel genes associated with exercise and calorie restriction effects in skeletal muscle (link)

  • NPJ Aging: Senescent cardiomyocytes contribute to cardiac dysfunction following myocardial infarction (link)

  • Proc Natl Acad Sci U S A: Leveraging single-cell RNA sequencing to unravel the impact of aging on stroke recovery mechanisms in mice (link)

  • Aging Cell: Whole-genome methylation analysis of aging human tissues identifies age-related changes in developmental and neurological pathways (link)

• Translational:

  • Lancet Child Adolesc Health: Association between the timing of childhood adversity and epigenetic patterns across childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort (link)

  • Psychol Med: Early life adversity predicts an accelerated cellular aging phenotype through early timing of puberty (link)

  • Nat Commun: Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection (link)

  • Nat Ecol Evol: Y chromosome toxicity does not contribute to sex-specific differences in longevity (link)

• Other:

  • Science: Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution (link)

  • Geroscience: Deconstructing heterogeneity of replicative senescence in human mesenchymal stem cells at single cell resolution (link)

  • Aging (Albany NY): Precious1GPT: multimodal transformer-based transfer learning for aging clock development and feature importance analysis for aging and age-related disease target discovery (link)

• Reviews:

  • J Gerontol A Biol Sci Med Sci: Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop (link)

  • J Clin Invest: Increased cell senescence in human metabolic disorders (link)

  • J Diabetes Investig: Is caloric restriction enough to increase longevity? Fasting and circadian alignment (link)

Model systems / Protocols

• Models:

  • ACS Biomater Sci Eng: Development of an Induced Pluripotent Stem Cell-Based Liver-on-a-Chip Assessed with an Alzheimer's Disease Drug (link)

  • Nat Protoc: Purification and functional characterization of novel human skeletal stem cell lineages (link)

  • Neurosci Lett: Modeling Enteric Glia Development, Physiology and Disease Using Human Pluripotent Stem Cells (link)

  • Physiol Genomics: Proteomics of novel iPSC-derived vascular endothelial cells reveal extensive similarity with an immortalized human endothelial cell line (link)

  • Cell Stem Cell: Organoid cultures for cancer modeling (link)

  • Nat Commun: Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme (link)

  • Stem Cell Reports: Organoids are not organs: Sources of variation and misinformation in organoid biology (link)

• Translational:

  • Circ Res: iPSC-Based Modeling of Variable Clinical Presentation in Hypertrophic Cardiomyopathy (link)

  • Stem Cell Reports: Enrichment of stem cell-derived pancreatic beta-like cells and controlled graft size through pharmacological removal of proliferating cells (link)

• Biomaterials:

  • J Control Release: Novel bilayer cell patch combining epidermal stem cells and angiogenic adipose stem cells for diabetic wound healing (link)

  • Adv Healthc Mater: Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner (link)

  • J Biomed Mater Res A: A highly versatile biopolymer-based platform for the maturation of human pluripotent stem cell-derived cardiomyocytes enables functional analysis in vitro and 3D printing of heart patches (link)

  • Adv Sci (Weinh): Extracellular Matrix/Glycopeptide Hybrid Hydrogel as an Immunomodulatory Niche for Endogenous Cardiac Repair after Myocardial Infarction (link)

Clinical

• Amino Acids: Age-associated polyamines in peripheral blood cells and plasma in 20 to 70 years of age subjects (link)

• Geroscience: Age-related changes in energy metabolism in peripheral mononuclear blood cells (PBMCs) and the brains of cognitively healthy seniors (link)

• Newly posted studies:

  • NCT05901818: Safety and Efficacy of Autologous iNSC-DAP in the Treatment of Parkinson's Disease (link)

  • NCT05897957: Continued Evaluation of Patients With Parkinson's Disease Who Previously Received BRT-DA01 (link)

Other (Articles, Perspectives, etc.)

• Nat Biotechnol: Why gene therapies must go virus-free (link)

• WSJ: What if the Most Powerful Way to Live Longer Is Just Exercise? (link)

• Financial:

  • Endpoints: Tissue regeneration biotech raises $26M Series A to push toward clinical trials (link)

  • Nat Rev Drug Discov: Upcoming market catalysts in Q3 2023 (link)

• Other interesting papers:

  • Nat Rev Drug Discov: Small-molecule discovery through DNA-encoded libraries (link)

With that in mind, Sana Biotechnology, a cell engineering company, recently announced adding autoimmune indications to its CD19 CAR-T SC291 clinical program. CD19 is a common B cell marker used to diagnose ALL, CLL, and other malignancies, but is also highly expressed in a variety of IgG and -M related disorders such as pemphigus vulgaris and systemic lupus (SLE) vs healthy controls. The idea is not new, and of course the pioneers at UPenn are developing a non-oncology CAR-T, but Sana may be the first US-based company to jump into the clinic with a broad CD19 CAR-T therapy for autoimmune disorders (Novartis has a single site in Spain; Cabaletta is using DSG3- and MuSK-CAARTs; and Cartesian is using a BCMA CAR-T). This short Twitter thread has some nice additional considerations.

For our purposes, a paper this week reviewed the potential of MSCs vs / together with CAR-Ts. Right now, a huge consideration for autologous CAR-Ts is the manufacturing cost and vein-to-vein time, while MSCs are inherently immunoprivileged and therefore benefit from allogeneic sourcing. Despite the decades of “promise” for MSCs, it is interesting that CAR-Ts have likely outsold all approved MSC therapies even though the first was only approved in 2017. Once the manufacturing and immune challenges are solved, there is a strong rationale for CAR-Ts to replace MSCs as the anti-inflammatory cell therapy of choice in the clinic.

As is common in science, it is rarely a “never” and more often a “when”.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

*Programming note: RegenMed Journal Club will be off next week, back June 19th

Top papers of the week (focus on brain models)

Nat Protoc: Medulloblastoma and high-grade glioma organoids for drug screening, lineage tracing, co-culture and in vivo assay (link)

Medulloblastoma and high-grade glioma represent the most aggressive and frequent lethal solid tumors affecting individuals during pediatric age. During the past years, several models have been established for studying these types of cancers. Human organoids have recently been shown to be a valid alternative model to study several aspects of brain cancer biology, genetics and test therapies. Notably, brain cancer organoids can be generated using genetically modified cerebral organoids differentiated from human induced pluripotent stem cells (hiPSCs). However, the protocols to generate them and their downstream applications are very rare. Here, we describe the protocols to generate cerebellum and forebrain organoids from hiPSCs, and the workflow to genetically modify them by overexpressing genes found altered in patients to finally produce cancer organoids. We also show detailed protocols to use medulloblastoma and high-grade glioma organoids for orthotopic transplantation and co-culture experiments aimed to study cell biology in vivo and in vitro, for lineage tracing to investigate the cell of origin and for drug screening. The protocol takes 60-65 d for cancer organoids generation and from 1-4 weeks for downstream applications. The protocol requires at least 3-6 months to become proficient in culturing hiPSCs, generating organoids and performing procedures on immunodeficient mice.

Lab Chip: Vascularized human brain organoid on-chip (link)

Modelling the human brain in vitro has been extremely challenging due to the brain's intricate cellular composition and specific structural architecture. The recent emergence of brain organoids that recapitulate many key features of human brain development has thus piqued the interest of many to further develop and apply this in vitro model for various physiological and pathological investigations. Despite ongoing efforts, the existing brain organoids demonstrate several limitations, such as the lack of a functional human vasculature with perfusion capability. Microfluidics is suited to enhance such brain organoid models by enabling vascular perfusion and a curated blood-brain barrier microenvironment. In this review, we first provide an introduction to in vivo human brain development and present the state-of-the-art in vitro human brain models. We further elaborate on different strategies to improve the vascularized human brain organoid microenvironment using microfluidic devices, while discussing the current obstacles and future directions in this field.

J Neurotrauma: Modelling the inflammatory response of traumatic brain injury using human induced pluripotent stem cell derived microglia (link)

The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterise the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified following human TBI. iPSC-derived microglia were exposed to IL-1β, IL-4, IL-6, IL-10 and TNF in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72-hour time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1β (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses to our previous studies of iPSC-derived neuronal and astrocyte cultures and the in-vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, as compared to astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.

Sci Transl Med: Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas (link)

Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1KO) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAFV600E/PTEN-/- and BRAFV600E/wt/PTEN-/- mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell- and T cell-mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SCN1KO-releasing GM-CSF and single-chain variable fragment anti-PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.

Stem cells / RegenMed

• NPJ Regen Med: Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke (link)

• J Cell Mol Med: Hypoxic preconditioned mesenchymal stem cells ameliorate rat brain injury after cardiopulmonary resuscitation by suppressing neuronal pyroptosis (link)

• Dis Model Mech: Immature human engineered heart tissues engraft in a guinea pig chronic injury model (link)

• J Am Heart Assoc: Heart Failure Impairs Bone Marrow Hematopoietic Stem Cell Function and Responses to Injury (link)

• Stem Cell Res Ther: MiR-146a-5p delivered by hucMSC extracellular vesicles modulates the inflammatory response to sulfur mustard-induced acute lung injury (link)

• Respir Res: Integrin α10β1-selected mesenchymal stem cells reduced hypercoagulopathy in a porcine model of acute respiratory distress syndrome (link)

• Exp Mol Med: Human induced neural stem cells support functional recovery in spinal cord injury models (link)

• Stem Cell Rev Rep: Inflammation Modifies miR-21 Expression Within Neuronal Extracellular Vesicles to Regulate Remyelination Following Spinal Cord Injury (link)

• Clin Sci (Lond): Restoration of the gut barrier integrity and restructuring of the gut microbiome in aging by Angiotensin-(1-7) (link)

• Stem Cell Res Ther: Intravenous injection of human umbilical cord-derived mesenchymal stem cells ameliorates not only blood glucose but also nephrotic complication of diabetic rats through autophagy-mediated anti-senescent mechanism (link)

• Stem Cell Res Ther: Human umbilical cord mesenchymal stem cell treatment alleviates symptoms in an atopic dermatitis-like mouse model (link)

• Sci Signal: The ubiquitin ligase Uhrf2 is a master regulator of cholesterol biosynthesis and is essential for liver regeneration (link)

• Reviews:

  • Eur J Haematol: Mesenchymal stromal cells and CAR-T cells in regenerative medicine: The homing procedure and their effective parameters (link)

  • Appl Microbiol Biotechnol: Mesenchymal and induced pluripotent stem cell-based therapeutics: a comparison (link)

  • Cell Transplant: Transplanting Microglia for Treating CNS Injuries and Neurological Diseases and Disorders, and Prospects for Generating Exogenic Microglia (link)

Aging / Longevity

• Aging Cell: Endothelial cell telomere dysfunction induces senescence and results in vascular and metabolic impairments (link)

• Geroscience: A metabolomic signature of decelerated physiological aging in human plasma (link)

• J Neuroinflammation: Analysis of the microglia transcriptome across the human lifespan using single cell RNA sequencing (link)

• Circ Res: An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis (link)

• Reviews:

  • Neurosci Bull: Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases (link)

  • PLoS Biol: Aging research: A field grows up (link)

  • Calcif Tissue Int: "Bone-SASP" in Skeletal Aging (link)

  • J Gerontol A Biol Sci Med Sci: Neurobiology of Aging: New Insights From Across the Research Spectrum (link)

Model systems / Protocols

• Models:

  • Biochem Soc Trans: Using human induced pluripotent stem cell-derived liver cells to investigate the mechanisms of liver fibrosis in vitro (link)

  • BMC Bioinformatics: CRISPR-GRANT: a cross-platform graphical analysis tool for high-throughput CRISPR-based genome editing evaluation (link)

• Translational:

  • Sci Transl Med: Constitutive IL-1RA production by modified immune cells protects against IL-1-mediated inflammatory disorders (link)

  • Stem Cell Rev Rep: Improving Autologous Fat Grafting in Regenerative Surgery through Stem Cell-Assisted Lipotransfer (link)

• Biomaterials:

  • ACS Biomater Sci Eng: Bilayer Silk Fibroin/Sodium Alginate Scaffold Delivered hUC-MSCs to Enhance Skin Scarless Healing and Hair Follicle Regeneration with the IRE1/XBP1 Pathway Inhibition (link)

  • J Cell Mol Med: Feasibility of repairing skin defects by VEGF165 gene-modified iPS-HFSCs seeded on a 3D printed scaffold containing astragalus polysaccharide (link)

Clinical

• Cell Stem Cell: Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery (link)

• Aging Cell: Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants (link)

• Eur J Haematol: Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study (link)

• J Bone Miner Res: Pro-inflammatory proteins associated with frailty and its progression - a longitudinal study in community dwelling women (link)

• Inflamm Bowel Dis: A Phase I Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Perianal Fistulizing Crohn's Disease (link)

• Newly posted studies:

  • NCT05881668: MSC-EV in Acute-on-Chronic Liver Failure After Liver Transplantation (link)

Other (Articles, Perspectives, etc.)

• Nat Biotechnol: Can microbes save the planet? (link)

• Financings:

  • Endpoints: Exclusive: With $8M, neuro startup Modulo Bio emerges to test small molecules for ALS, dementia in CEO’s personal mission (link)

• Other interesting papers:

  • Sci Rep: Ultra-low-cost mechanical smartphone attachment for no-calibration blood pressure measurement (link)

  • Nat Rev Gastroenterol Hepatol: A Roadmap for the Human Gut Cell Atlas (link)

  • Science: A global catalog of whole-genome diversity from 233 primate species (link)

  • Science: The landscape of tolerated genetic variation in humans and primates (link)

While PubMed identifies “longevity” articles going back to 1786, the publication numbers have only gone parabolic in the last ~15 years. With this comes the inevitable profiling of some of the most extreme characters and situations, where particularly in fields like finance and healthcare these articles are instant clickbait (think profiles on Elizabeth Holmes, Martin Shkreli, and SBF), but may cast a pall over the benefits and goals of a movement.

This is why I was so relieved to see Peter Attia’s recent rationale and relatable interview in the NYT Magazine. Dr. Attia’s humility, experience, and data came across naturally as the interviewer looked to understand the field of longevity while appropriately challenging topics such as costs, time commitments, and fanatical behavior.

Dr. Attia has been featured on the Invest Like The Best podcast a couple times (2018 here; 2023 here) and one point that really hit home was his idea of a centenarian decathlon: what do you want to be able to do at 100 years old, and how do ready yourself today? Some of Dr. Attia’s desires are to lift a 30lb grandchild, put a suitcase in a plane’s overhead compartment, and stand up from the floor without assistance. Nothing extreme! But the mindset of compounding your wellbeing has to be fostered today.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week (focus on hypoxia/ischemia)

PLoS Biol: Hypoxia extends lifespan and neurological function in a mouse model of aging (link)

There is widespread interest in identifying interventions that extend healthy lifespan. Chronic continuous hypoxia delays the onset of replicative senescence in cultured cells and extends lifespan in yeast, nematodes, and fruit flies. Here, we asked whether chronic continuous hypoxia is beneficial in mammalian aging. We utilized the Ercc1 Δ/- mouse model of accelerated aging given that these mice are born developmentally normal but exhibit anatomic, physiological, and biochemical features of aging across multiple organs. Importantly, they exhibit a shortened lifespan that is extended by dietary restriction, the most potent aging intervention across many organisms. We report that chronic continuous 11% oxygen commenced at 4 weeks of age extends lifespan by 50% and delays the onset of neurological debility in Ercc1 Δ/- mice. Chronic continuous hypoxia did not impact food intake and did not significantly affect markers of DNA damage or senescence, suggesting that hypoxia did not simply alleviate the proximal effects of the Ercc1 mutation, but rather acted downstream via unknown mechanisms. To the best of our knowledge, this is the first study to demonstrate that "oxygen restriction" can extend lifespan in a mammalian model of aging.

Stem Cells Transl Med: Transplantation of Human Brain-Derived Ischemia-Induced Multipotent Stem Cells Ameliorates Neurological Dysfunction in Mice After Stroke (link)

We recently demonstrated that injury/ischemia-induced multipotent stem cells (iSCs) develop within post-stroke human brains. Because iSCs are stem cells induced under pathological conditions, such as ischemic stroke, the use of human brain-derived iSCs (h-iSCs) may represent a novel therapy for stroke patients. We performed a preclinical study by transplanting h-iSCs transcranially into post-stroke mouse brains 6 weeks after middle cerebral artery occlusion (MCAO). Compared with PBS-treated controls, h-iSC transplantation significantly improved neurological function. To identify the underlying mechanism, green fluorescent protein (GFP)-labeled h-iSCs were transplanted into post-stroke mouse brains. Immunohistochemistry revealed that GFP+ h-iSCs survived around the ischemic areas and some differentiated into mature neuronal cells. To determine the effect on endogenous neural stem/progenitor cells (NSPCs) by h-iSC transplantation, mCherry-labeled h-iSCs were administered to Nestin-GFP transgenic mice which were subjected to MCAO. As a result, many GFP+ NSPCs were observed around the injured sites compared with controls, indicating that mCherry+ h-iSCs activate GFP+ endogenous NSPCs. In support of these findings, coculture studies revealed that the presence of h-iSCs promotes the proliferation of endogenous NSPCs and increases neurogenesis. In addition, coculture experiments indicated neuronal network formation between h-iSC- and NSPC-derived neurons. These results suggest that h-iSCs exert positive effects on neural regeneration through not only neural replacement by grafted cells but also neurogenesis by activated endogenous NSPCs. Thus, h-iSCs have the potential to be a novel source of cell therapy for stroke patients.

Cell Death Discov: Adipose mesenchymal stem cell-derived soluble factors, produced under hypoxic condition, efficiently support in vivo angiogenesis (link)

Tissue regeneration or healing both require efficient vascularization within a tissue-damaged area. Based on this concept, a remarkable number of strategies, aimed at developing new tools to support re-vascularization of damaged tissue have emerged. Among the strategies proposed, the use of pro-angiogenic soluble factors, as a cell-free tool, appears as a promising approach, able to overcome the issues concerning the direct use of cells for regenerative medicine therapy. Here, we compared the effectiveness of adipose mesenchymal stem cells (ASCs), use as cell suspension, ASC protein extract or ASC-conditioned-medium (i.e., soluble factors), combined with collagenic scaffold, in supporting in vivo angiogenesis. We also tested the capability of hypoxia in increasing the efficiency of ASC to promote angiogenesis, via soluble factors, both in vivo and in vitro. In vivo studies were performed using the Integra® Flowable Wound Matrix, and the Ultimatrix in sponge assay. Flow cytometry was used to characterize the scaffold- and sponge-infiltrating cells. Real-time PCR was used to evaluate the expression of pro-angiogenic factors by stimulating Human Umbilical-Vein Endothelial Cells with ASC-conditioned media, obtained in hypoxic and normoxic conditions. We found that, in vivo, ACS-conditioned media can support angiogenesis similar to ASCs and ASC protein extract. Also, we observed that hypoxia increases the pro-angiogenic activities of ASC-conditioned media, compared to normoxia, by generating a secretome enriched in pro-angiogenic soluble factors, with bFGF, Adiponectine, ENA78, GRO, GRO-a, and ICAM1-3, as most regulated factors. Finally, ASC-conditioned media, produced in hypoxic condition, induce the expression of pro-angiogenic molecules in HUVECs. Our results provide evidence that ASC-conditioned-medium can be proposed as a cell-free preparation able to support angiogenesis, thus providing a relevant tool to overcome the issues and restrictions associated with the use of cells.

Arterioscler Thromb Vasc Biol: Hypoxia-Preconditioned Bone Marrow Mesenchymal Stem Cells Improved Cerebral Collateral Circulation and Stroke Outcome in Mice (link)

Background: Adequate collateral circulation can remarkably improve patient prognoses for patients experiencing ischemic stroke. Hypoxic preconditioning enhances the regenerative properties of bone marrow mesenchymal stem cells (BMSCs). Rabep2 (RAB GTPase binding effector protein 2) is a key protein in collateral remodeling. We investigated whether BMSCs and hypoxia-preconditioned BMSCs (H-BMSCs) augment collateral circulation poststroke, particularly through Rabep2 regulation.

Methods: BMSCs or H-BMSCs (1×10⁶) were delivered intranasally in ischemic mice with distal middle cerebral artery occlusion at 6 hours poststroke. Two-photon microscopic imaging and vessel painting methods were used to analyze collateral remodeling. Blood flow, vascular density, infarct volume, and gait analysis were assessed to evaluate poststroke outcomes. Expressions of proangiogenic marker VEGF (vascular endothelial growth factor) and Rabep2 were determined by Western blotting. Western blot, EdU incorporation, and tube formation assays were conducted on cultured endothelial cells treated with BMSCs.

Results: BMSCs were more effectively transplanted in the ischemic brain after hypoxic preconditioning. The ipsilateral collateral diameter was increased by BMSCs and strengthened by H-BMSCs (P<0.05). BMSCs increased peri-infarct blood flow and vascular density and reduced infarct volume, gait deficits (P<0.05), and furthermore by H-BMSCs (P<0.05). VEGF and Rabep2 protein expression was increased by BMSCs (P<0.05), which was enhanced by preconditioning (P<0.01). Additionally, BMSCs increased Rabep2 expression, proliferation, and tube formation of endothelial cells in vitro (P<0.05). H-BMSCs enhanced these effects (P<0.05), which were annulled by Rabep2 knockdown.

Conclusions: BMSCs increased collateral circulation and improved poststroke outcomes, through the upregulation of Rabep2. These effects were enhanced by hypoxic preconditioning.

Stem cells / RegenMed

• EMBO Rep: mTORC1 activity negatively regulates human hair follicle growth and pigmentation (link)

• Proc Natl Acad Sci U S A: MicroRNA-205 promotes hair regeneration by modulating mechanical properties of hair follicle stem cells (link)

• Nat Commun: Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles (link)

• Development: The translation initiation factor homolog, eif4e1c, regulates cardiomyocyte metabolism and proliferation during heart regeneration (link)

• Stem Cell Res Ther: Mesenchymal stem/stromal cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model (link)

• Proc Natl Acad Sci U S A: Regenerative engineering of long bones using the small molecule forskolin (link)

• Ren Fail: Periosteum-derived mesenchymal stem cell alleviates renal fibrosis through mTOR-mediated Treg differentiation (link)

• Sci Adv: Charting a high-resolution roadmap for regeneration of pancreatic β cells by in vivo transdifferentiation from adult acinar cells (link)

• Elife: Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration (link)

• NPJ Regen Med: A superior extracellular matrix binding motif to enhance the regenerative activity and safety of therapeutic proteins (link)

• Reviews:

  • Antioxid Redox Signal: Perish in the attempt: regulated cell death in regenerative and non-regenerative tissue (link)

  • Inflamm Regen: Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy (link)

  • Stem Cell Res Ther: Cell therapy in end-stage liver disease: replace and remodel (link)

Aging / Longevity

• Proc Natl Acad Sci U S A: Stem cell decoupling underlies impaired lymphoid development during aging (link)

• NPJ Aging: Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models (link)

• Cell Death Dis: Accelerated aging in articular cartilage by ZMPSTE24 deficiency leads to osteoarthritis with impaired metabolic signaling and epigenetic regulation (link)

• Aging Cell: The initial age-associated decline in early T-cell progenitors reflects fewer pre-thymic progenitors and altered signals in the bone marrow and thymus microenvironments (link)

• Aging Cell: Young donor hematopoietic stem cells revitalize aged or damaged bone marrow niche by transdifferentiating into functional niche cells (link)

• Sci Rep: Spermidine improves angiogenic capacity of senescent endothelial cells, and enhances ischemia-induced neovascularization in aged mice (link)

• Traffic: Deacidification of endolysosomes by neuronal aging drives synapse loss (link)

• Reviews:

  • J Am Geriatr Soc: The determinants of longevity: The perspectives from East Asian economies (link)

Model systems / Protocols

• Models:

  • Lab Chip: Ce Lab, a microfluidic platform for the study of life history traits, reveals metformin and SGK-1 regulation of longevity and reproductive span (link)

  • Cell Rep: Modeling human ectopic pregnancies with trophoblast and vascular organoids (link)

  • Sci Rep: Simple and efficient differentiation of human iPSCs into contractible skeletal muscles for muscular disease modeling (link)

  • Nat Commun: Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche (link)

  • Stem Cells: Modulation of WNT, Activin/Nodal and MAPK Signaling Pathways Increases Arterial Hemogenic Endothelium and Hematopoietic Stem/Progenitor Cell Formation During Human iPSC Differentiation (link)

• Translational:

  • ACS Appl Mater Interfaces: Scalable and Uniform Fabrication of Dexamethasone-Eluting Depot-Engineered Stem Cell Spheroids as a Microtissue Construct to Target Bone Regeneration (link)

  • Stem Cells Transl Med: Propensity of Patient-Derived iPSCs for Retinal Differentiation: Implications for Autologous Cell Replacement (link)

  • Am J Sports Med: Cryopreserved Adipose-Derived Stem Cell Sheets: An Off-the-Shelf Scaffold for Augmenting Tendon-to-Bone Healing in a Rabbit Model of Chronic Rotator Cuff Tear (link)

• Biomaterials:

  • Acta Biomater: Special Issue on Biofabrication with Spheroid and Organoid Materials (link)

  • Adv Sci (Weinh): Melanin-Integrated Structural Color Hybrid Hydrogels for Wound Healing (link)

  • Adv Healthc Mater: High-Throughput Bioprinting of Geometrically-Controlled Pre-Vascularized Injectable Microgels for Accelerated Tissue Regeneration (link)

  • Adv Mater: Mechanical Signal-Tailored Hydrogel Microspheres Recruit and Train Stem Cells for Precise Differentiation (link)

  • Biomater Sci: Cellular modifications and biomaterial design to improve mesenchymal stem cell transplantation (link)

Clinical

• Diabetologia: Umbilical cord-derived mesenchymal stromal cells preserve endogenous insulin production in type 1 diabetes: a Phase I/II randomised double-blind placebo-controlled trial (link)

• Expert Rev Neurother: Clinical trials for neuroregenerative therapies for spinal cord injury: what have we learnt so far? (link)

• Newly posted studies:

  • NCT05870462: Semaglutide and Vascular Regeneration (SEMA-VR) (link)

  • NCT05871463: Effect of Mesenchymal Stem Cells-derived Exosomes in Decompensated Liver Cirrhosis (link)

  • NCT05872659: Mesenchymal Stem Cells for Immune Non-responder Patients With HIV Infection (link)

  • NCT05877300: Safety and Feasibility Study of the CELLSPAN Esophageal Implant (CEI) in Patients Requiring Short Segment Esophageal Replacement (link)

Other (Articles, Perspectives, etc.)

• Nature: How mixing academia and industry opens doors in graduate school and beyond (link)

• Science: Emerging frontiers in regenerative medicine (link)

• Financings:

  • Heartseed: Heartseed raises 2 billion JPY in series D funding to accelerate development of iPSC-derived stem cell therapy for heart failure (link)

  • FinSMEs: RedDress, a Tel Aviv, Israel-based personalized and autologous wound management solution created from patients own blood, raised $26M in Series D funding (link)

• Other interesting papers:

  • Nature: Walking naturally after spinal cord injury using a brain–spine interface (link)

  • Sci Adv: Living microecological hydrogels for wound healing (link)

  • Haemophilia: Acceptability of prenatal diagnosis and prenatal treatment of haemophilia using cell and gene therapies within US haemophilia community (link)

Semaglutide, and GLP-1s generally, have been heralded as a new panacea in weight loss and longevity (and addiction?). This is not wrong, but is wildly overstating the drug’s potential. For one, in 2021 there was another study published in NEJM showing a new GLP-1/GIP agonist tirzepatide (now approved as Mounjaro) significantly outperformed semaglutide in T2D patients (open label trial, but the clinical data in the label is superior). This indicates semaglutide may not be the best option for many patients, even before it goes off patent.

Second, the grandfather of longevity drugs metformin also acts partly as a GLP-1 agonist, indicating semaglutide should have longevity benefits but in no novel sense. In fact, the longevity is mainly due to reductions in comorbid mortality by reducing whole-body strain from overweight or obesity (i.e., reductions in MACE). There is evidence semaglutide also acts on the mTORC1 / AMPK pathway similar to metformin, but so do other GLP-1s like liraglutide and of course much safer and longer-studied molecules like rapamycin. (Semaglutide has not yet been tested in the NIA’s ITP which is the ultimate arbiter.)

I’ll say here what I said at the birthday party: semaglutide is an amazing drug that has helped and will continue to help millions of people, but to argue it is the one drug to rule them all risks running afoul of the Vitamin C fallacy. I was, as usual, a bit long-winded considering the audience and setting, but we all settled down with cake and donuts so perhaps semaglutide has a bright future yet.

As always, please feel free to reach out with any questions, comments, or otherwise. Enjoy the read.

-EDM

Top papers of the week

Science: Interplay between calcium and sarcomeres directs cardiomyocyte maturation during regeneration (link)

Zebrafish hearts can regenerate by replacing damaged tissue with new cardiomyocytes. Although the steps leading up to the proliferation of surviving cardiomyocytes have been extensively studied, little is known about the mechanisms that control proliferation and redifferentiation to a mature state. We found that the cardiac dyad, a structure that regulates calcium handling and excitation-contraction coupling, played a key role in the redifferentiation process. A component of the cardiac dyad called leucine-rich repeat-containing 10 (Lrrc10) acted as a negative regulator of proliferation, prevented cardiomegaly, and induced redifferentiation. We found that its function was conserved in mammalian cardiomyocytes. This study highlights the importance of the underlying mechanisms required for heart regeneration and their application to the generation of fully functional cardiomyocytes..

Nat Microbiol: Centenarians have a diverse gut virome with the potential to modulate metabolism and promote healthy lifespan (link)

Distinct gut microbiome ecology may be implicated in the prevention of aging-related diseases as it influences systemic immune function and resistance to infections. Yet, the viral component of the microbiome throughout different stages in life remains unexplored. Here we present a characterization of the centenarian gut virome using previously published metagenomes from 195 individuals from Japan and Sardinia. Compared with gut viromes of younger adults (>18 yr) and older individuals (>60 yr), centenarians had a more diverse virome including previously undescribed viral genera, such as viruses associated with Clostridia. A population shift towards higher lytic activity was also observed. Finally, we investigated phage-encoded auxiliary functions that influence bacterial physiology, which revealed an enrichment of genes supporting key steps in sulfate metabolic pathways. Phage and bacterial members of the centenarian microbiome displayed an increased potential for converting methionine to homocysteine, sulfate to sulfide and taurine to sulfide. A greater metabolic output of microbial hydrogen sulfide in centenarians may in turn support mucosal integrity and resistance to pathobionts.

Cell Transplant: In Vivo Delivery of Therapeutic Molecules by Transplantation of Genome-Edited Induced Pluripotent Stem Cells (link)

Human induced pluripotent stem cells (iPSCs) have already been used in transplantation therapies. Currently, cells from healthy people are transplanted into patients with diseases. With the rapid evolution of genome editing technology, genetic modification could be applied to enhance the therapeutic effects of iPSCs, such as the introduction of secreted molecules to make the cells a drug delivery system. Here, we addressed this possibility by utilizing a Fabry disease mouse model, as a proof of concept. Fabry disease is caused by the lack of α-galactosidase A (GLA). We previously developed an immunotolerant therapeutic molecule, modified α-N-acetylgalactosaminidase (mNAGA). We confirmed that secreted mNAGA from genome-edited iPSCs compensated for the GLA activity in GLA-deficient cells using an in vitro co-culture system. Moreover, iPSCs transplanted into Fabry model mice secreted mNAGA and supplied GLA activity to the liver. This study demonstrates the great potential of genome-edited iPSCs secreting therapeutic molecules.

Stem cells / RegenMed

• Cell Transplant: Pericardial Grafting of Cardiac Progenitor Cells in Self-Assembling Peptide Scaffold Improves Cardiac Function After Myocardial Infarction (link)

• J Clin Invest: Cardiac pericytes mediate the remodeling response to myocardial infarction (link)

• Mol Biol Rep: Mitoprotective effect of mesenchymal stem cells-derived conditioned medium in myocardial reperfusion injury of aged rats: role of SIRT-1/PGC-1α/NRF-2 network (link)

• Cell Prolif: 3D bioprinting microgels to construct implantable vascular tissue (link)

• PLoS One: Dose-dependent modulation of microglia activation in rats after penetrating traumatic brain injury (pTBI) by transplanted human neural stem cells (link)

• Stem Cells Transl Med: Metformin Improves Functional Outcomes, Activates Neural Precursor Cells, and Modulates Microglia in a Sex-Dependent Manner After Spinal Cord Injury (link)

• Nat Cell Biol: Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification (link)

• Stem Cell Res Ther: CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration (link)

• Cell Res: Lin28a maintains a subset of adult muscle stem cells in an embryonic-like state (link)

• Proc Natl Acad Sci U S A: Harnessing endogenous transcription factors directly by small molecules for chemically induced pluripotency inception (link)

• Reviews:

  • Stem Cell Res Ther: Electromagnetic fields regulate calcium-mediated cell fate of stem cells: osteogenesis, chondrogenesis and apoptosis (link)

  • Adv Sci (Weinh): Cell-Based Therapies for Degenerative Musculoskeletal Diseases (link)

Aging / Longevity

• Sci Transl Med: Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging (link)

• Cell Prolif: SESN1 is a FOXO3 effector that counteracts human skeletal muscle ageing (link)

• PLoS One: Loss of transcriptional heterogeneity in aged human muscle stem cells (link)

• Nat Immunol: Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology (link)

• Aging Dis: KRT5+/p63+ Stem Cells Undergo Senescence in the Human Lung with Pathological Aging (link)

• J Cell Sci: Oxidative stress induces chromosomal instability through replication stress in fibroblasts from aged mice (link)

• Genome Biol: Phenome-wide analyses identify an association between the parent-of-origin effects dependent methylome and the rate of aging in humans (link)

• Pharmacol Res Perspect: Rapamycin treatment increases survival, autophagy biomarkers and expression of the anti-aging klotho protein in elderly mice (link)

• Reviews:

  • Aging Dis: Conceptual Overview of Biological Age Estimation (link)

  • Aging Dis: Extracellular Matrix Dynamics as an Emerging yet Understudied Hallmark of Aging and Longevity (link)

  • Nat Rev Cardiol: Hallmarks of cardiovascular ageing (link)

  • Ageing Res Rev: Mitochondrial dysfunction in aging (link)