Cell Stem Cell

Hypoxia promotes airway differentiation in the human lung epithelium Dong and colleagues uncover low oxygen-directed differentiation of human lung progenitors to airway rather than alveolar fate and show how the process is controlled by hypoxia-inducible factors. Hypoxia also converts differentiated alveolar cells into airway-like cells. Hypoxia is therefore both a developmental cue and a pathological factor in human lungs.

Online Now! Hypoxia promotes airway differentiation in the human lung epithelium #stemcells

Building the start: Unlocking advanced stem cell-based embryo models Two recent studies from the Silva and Hanna groups optimized chemical induction and culture conditions to derive extraembryonic lineages directly from embryonic stem cells (ESCs) without transgenes, enabling mouse stem cell-based embryo models (SCBEMs) to reproducibly advance to the E8.5–E8.75 stage.

Building the start: Unlocking advanced stem cell-based embryo models

Raising the bar for human post-implantation embryo models The generation of stem-cell-based embryo models has ushered in a new era for human embryology, but improving their reproducibility and lineage fidelity has remained a challenge. In this issue of Cell Stem Cell, Chen et al. and Oura et al. develop refined strategies to assemble human post-implantation embryo models with greater accuracy and efficiency, setting a new standard for the field.

Raising the bar for human post-implantation embryo models

Unmasking cancer’s hidden nerve route with patient-derived organoids Chan et al. show that enteric neurons influence lipid metabolism in gastric cancer organoids, affecting dependencies on key enzymes. Using CRISPR screening and metabolic analysis, their work highlights how microenvironmental signals impact tumor metabolism and potential treatment targets in gastric cancer.

Unmasking cancer’s hidden nerve route with patient-derived organoids

Mind, mood and new neurons: Probing adult hippocampal neurogenesis in neuropsychiatry and beyond In this issue of Cell Stem Cell, Márquez-Valadez, Gallardo-Caballero, and Llorens-Martín1 report that adult hippocampal neurogenesis (AHN) is differentially disrupted in neuropsychiatric disorders. Their findings highlight the role of the neurogenic niche and lifestyle, supporting the view of human AHN as a dynamic process sensitive to biology and behavior.

Mind, mood and new neurons: Probing adult hippocampal neurogenesis in neuropsychiatry and beyond

From form to function: New heights in kidney organoids In this issue of Cell Stem Cell, Huang et al. address the challenge of creating organoids that more closely replicate kidney spatial patterning and function. They develop region-specific progenitor assembloids mimicking native architecture. After transplantation into mice, which further promotes differentiation, they demonstrate functional and disease modeling capability.

From form to function: New heights in kidney organoids

From sentinels to engineers: The future of microglia in brain regeneration Recent studies highlight microglial replacement as a promising therapeutic approach for neurological disease. Wu et al. demonstrated that transplanted bone marrow–derived cells halted ALSP progression, while Mader et al. introduced a strategy that avoids systemic bone marrow ablation toxicity and reduces immune rejection, collectively validating this strategy’s therapeutic potential.

From sentinels to engineers: The future of microglia in brain regeneration

Stem cell research in space: Advancing regenerative medicine beyond Earth Spaceflight provides a unique environment that profoundly influences stem cell biology. Experiments aboard the International Space Station (ISS) and in simulated microgravity have revealed altered stem cell proliferation, differentiation, and stress responses, unveiling possibilities for modeling impacts of spaceflight and harnessing microgravity for biomanufacturing. Stem cell-derived organoids and tissue models flown in space are yielding insights into development, disease, and aging mechanisms, while in-space biomanufacturing efforts demonstrate accelerated stem cell expansion and tissue formation for potential translational and clinical applications.

Stem cell research in space: Advancing regenerative medicine beyond Earth

Targeting lysozyme 2 in endocardium promotes rapid recovery by modulating remote injury signals

Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling Recapitulating the self-assembly of kidney progenitors, Huang, Medina, He, Zeng, and colleagues have developed mouse and human kidney progenitor assembloids, exhibiting enhanced cellular complexity, spatial organization, maturation, and functional capacity. These sophisticated models provide high-fidelity platforms for disease modeling and establish a robust foundation for kidney regenerative medicine.

Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling

Signaling reprogramming via Stat3 activation unravels high-fidelity human post-implantation embryo modeling Enhanced STAT3 activation combined with TGF-β inhibition reprograms human PSCs into cells specifying all early embryonic lineages. Upon 3D suspension culture, these cells self-organize within 6 days into post-implantation structures mimicking Carnegie stages 5–7 embryos, including gastrulation, with high morphological and molecular fidelity.

Signaling reprogramming via Stat3 activation unravels high-fidelity human post-implantation embryo modeling

Human adult hippocampal neurogenesis is shaped by neuropsychiatric disorders, demographics, and lifestyle-related factors Márquez-Valadez and colleagues show that neuropsychiatric disorders alter the generation of new neurons in the adult human brain. Major depression, schizophrenia, and bipolar disorder disrupt early stages of hippocampal neurogenesis and its supportive environment, with lifestyle factors further modulating these effects—even in healthy individuals.

Human adult hippocampal neurogenesis is shaped by neuropsychiatric disorders, demographics, and lifestyle-related factors

Adopting novel alternative methods (NAMs) for biomedical research—What is the right approach? The field of medical science has relied on animal models to both establish fundamental biological principles and test new drugs prior to human administration for over 100 years. Given the significant differences between mice and humans, the relevance of these data has often been a concern to scientists. Recently, the development of induced pluripotent stem cells (iPSCs), organoids, and new bioengineering techniques along with advancing artificial intelligence (AI) has reached a tipping point—coming close to providing more reliable, relevant ways to understand human biology and help drug development.

Adopting novel alternative methods (NAMs) for biomedical research—What is the right approach?

A combined enteric neuron-gastric tumor organoid reveals metabolic vulnerabilities in gastric cancer Chan and colleagues use CRISPR screens in patient-derived tumor organoids to reveal metabolic vulnerabilities not seen in 2D and 3D spheroid models and identify potent inhibitors that target gastric cancer’s lipid metabolism. A neuron-cancer coculture screen found that ACC level predicts treatment efficacy, highlighting neuronal interaction in cancer lipid reliance.

A combined enteric neuron-gastric tumor organoid reveals metabolic vulnerabilities in gastric cancer

An inducible model of human post-implantation development derived from primed and naive stem cells Wu and colleagues developed inducible stem cell-based embryo models (iSCBEMs) that recapitulate key features of early post-implantation development, corresponding to Carnegie stages 5–6 (CS5–CS6). iSCBEMs offer a robust and accessible platform for studying this critical window, revealing new insights into the cellular origins of the yolk sac and extraembryonic mesenchyme.

An inducible model of human post-implantation development derived from primed and naive stem cells

Transgene-free generation of mouse post-gastrulation whole embryo models solely from naive ESCs and iPSCs Hanna and colleagues show that signaling pathway modulation amplifies the inherent flexibility of genetically unmodified mouse naive PSCs to adopt extra-embryonic cell fate potential. This endows them with the competence to generate up to E8.5–E8.75 transgene-free stem cell-derived embryo models (TF-SEMs) that complete gastrulation and initiate organogenesis within complex extra-embryonic compartments ex utero.

Transgene-free generation of mouse post-gastrulation whole embryo models solely from naive ESCs and iPSCs

Online Now! A mineralizing pool of Gli1-expressing progenitors builds the tendon enthesis and demonstrates therapeutic potential #stemcells

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Check out the science we have planned @CellSymposia #CSStemCells2025 from sessions on Cell replacement therapy; Emerging immune approaches; Aging & rejuvenation; Gene therapy; and Therapeutic screening. View the program and register: http://dlvr.it/TNJjYz

Nuestra investigadora María Llorens explica su último trabajo, publicado hoy en @cp-cellstemcell.bsky.social: Las enfermedades psiquiátricas y el consumo de alcohol y drogas limitan la generación de nuevas neuronas en el cerebro. Léelo: www.cbm.uam.es/index.php/20... @csic.es @uam.es

Targeting lysozyme 2 in endocardium promotes rapid recovery by modulating remote injury signals Fan et al. discovered that local cardiac injury triggers aberrant lysozyme 2 (Lyz2) expression in remote zones. Lyz2 acts as a remote-injury-triggered regulator of lysosomal degradation in endocardial cells, driving pathogenic extracellular matrix breakdown. Inhibiting the LYZ2-mediated injury response—via knockout or pharmacological lysosomal inhibition—confers rapid functional recovery of non-regenerative hearts.

Online Now! Targeting lysozyme 2 in endocardium promotes rapid recovery by modulating remote injury signals #stemcells

Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling Recapitulating the self-assembly of kidney progenitors, Huang, Medina, He, Zeng, and colleagues have developed mouse and human kidney progenitor assembloids, exhibiting enhanced cellular complexity, spatial organization, maturation, and functional capacity. These sophisticated models provide high-fidelity platforms for disease modeling and establish a robust foundation for kidney regenerative medicine.

Online Now! Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling #stemcells

Safety and tolerability of RPESC-RPE transplantation in patients with dry age-related macular degeneration: Low-dose clinical outcomes Retinal pigment epithelium (RPE) cell loss in dry age-related macular degeneration leads to progressive vision decline. Stern and others implanted adult RPE stem cell-derived RPE progeny at a 4-week progenitor stage of differentiation (RPESC-RPE-4W). First-in-human cohort 1 met primary safety endpoints, with greater visual improvement observed in worse-seeing eyes.

Online Now! Safety and tolerability of RPESC-RPE transplantation in patients with dry age-related macular degeneration: Low-dose clinical outcomes #stemcells

Signaling reprogramming via Stat3 activation unravels high-fidelity human post-implantation embryo modeling Enhanced STAT3 activation combined with TGF-β inhibition reprograms human PSCs into cells specifying all early embryonic lineages. Upon 3D suspension culture, these cells self-organize within 6 days into post-implantation structures mimicking Carnegie stages 5–7 embryos, including gastrulation, with high morphological and molecular fidelity.

Online Now! Signaling reprogramming via Stat3 activation unravels high-fidelity human post-implantation embryo modeling #stemcells

Congratulations to Rudolf Jaenisch, MD, recipient of the 2025 Ogawa-Yamanaka Stem Cell Prize by Gladstone Institutes (@‌GladstoneInst) who was selected for his trailblazing contributions to epigenetics and stem cell biology.
Read more: gladstone.org/news/2025-og...

Human adult hippocampal neurogenesis is shaped by neuropsychiatric disorders, demographics, and lifestyle-related factors Márquez-Valadez and colleagues show that neuropsychiatric disorders alter the generation of new neurons in the adult human brain. Major depression, schizophrenia, and bipolar disorder disrupt early stages of hippocampal neurogenesis and its supportive environment, with lifestyle factors further modulating these effects—even in healthy individuals.

Online Now! Human adult hippocampal neurogenesis is shaped by neuropsychiatric disorders, demographics, and lifestyle-related factors #stemcells

Adopting novel alternative methods (NAMs) for biomedical research—What is the right approach? The field of medical science has relied on animal models to both establish fundamental biological principles and test new drugs prior to human administration for over 100 years. Given the significant differences between mice and humans, the relevance of these data has often been a concern to scientists. Recently, the development of induced pluripotent stem cells (iPSCs), organoids, and new bioengineering techniques along with advancing artificial intelligence (AI) has reached a tipping point—coming close to providing more reliable, relevant ways to understand human biology and help drug development.

Online Now! Adopting novel alternative methods (NAMs) for biomedical research—What is the right approach? #stemcells

Severing the scar supply line: CAR-T in chronic kidney disease CAR-T cell therapy is rapidly being extended to target various pathophysiological processes beyond cancer. In this issue of Cell Stem Cell, Zhao et al. engineered PDGFRβ-specific CAR-T cells in vivo to selectively target extracellular matrix-producing cells in kidney fibrosis, opening new opportunities for treating fibrotic diseases with precision immunotherapy.

Severing the scar supply line: CAR-T in chronic kidney disease

From β soloist to endocrine symphony: Subtype-complete islets conduct glucose harmony While current stem cell differentiation protocols generate β cell-enriched islets that reverse hyperglycemia post-implantation, they can cause hypoglycemia. Meng et al. reconstruct endocrine subtype-complete islets, which restore counterregulatory responses and protect against hypoglycemia in diabetic mice, highlighting the importance of endocrine diversity in designing physiologically regulated cell therapies for diabetes.

From β soloist to endocrine symphony: Subtype-complete islets conduct glucose harmony

Engineered VTA dopaminergic neurons offer a new path to treating depression Dysfunction of A10 midbrain dopaminergic (mDA) neurons is linked to psychiatric disorders, such as depression. In this issue, Yan et al. present an efficient method for differentiating human pluripotent stem cells into A10-like mDA neurons. Activation of grafted A10-like neurons into the mouse mesolimbic circuit alleviates depression-like symptoms.

Engineered VTA dopaminergic neurons offer a new path to treating depression

Ready, set, but no go: Skin fat comes preloaded with waiting precursors Fat depots across the body dynamically tune their sizes in response to nutrient demands and nonmetabolic cues. Writing in Cell Stem Cell, Rivera-Gonzalez et al. report that skin fat, notable for its ability to rapidly expand, harbors molecularly distinct precursors, primed for proliferation and differentiation into mature adipocytes.

Ready, set, but no go: Skin fat comes preloaded with waiting precursors