In mice, the repressive histone mark H3K27me3 undergoes both region-specific inheritance and erasure during the parental-to-embryonic transition, with the underlying mechanisms poorly understood. Here, we show that PRC2, which catalyzes H3K27me3, binds both classic Polycomb targets and noncanonical H3K27me3 domains in growing oocytes but dissociates from chromatin in fully grown oocytes. After fertilization, PRC2 rebinds noncanonical H3K27me3 domains before relocating to Polycomb targets in blastocysts. Interestingly, the binding and activity of PRC2 are restricted by a maternal inhibitory factor, EZH inhibitory protein (EZHIP), which co-binds with PRC2. Upon knockout of Ezhip, hyperactive PRC2 promiscuously deposits H3K27me3 genome-wide. This overwrites H3K27me3 memories at noncanonical imprinted genes and paradoxically causes derepression of H3K27me3 targets, defective X chromosome inactivation, and diluted chromatin PRC2. H3K27me3 restoration at Polycomb targets after implantation is also attenuated, accompanied by sub-lethality. These data unveil principles of epigenetic inheritance that both insufficient and excessive heterochromatic marks cause loss of epigenetic memories and repression.
{"title":"EZHIP restricts noncanonical PRC2 binding and regulates H3K27me3 intergenerational inheritance and reprogramming.","authors":"Yitian Zeng,Feng Kong,Zihan Xu,Xukun Lu,Qian Li,Bofeng Liu,Shu Liu,Lijun Dong,Ling Liu,Wenying Wang,Bing Zhu,Wei Xie","doi":"10.1016/j.stem.2025.09.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.009","url":null,"abstract":"In mice, the repressive histone mark H3K27me3 undergoes both region-specific inheritance and erasure during the parental-to-embryonic transition, with the underlying mechanisms poorly understood. Here, we show that PRC2, which catalyzes H3K27me3, binds both classic Polycomb targets and noncanonical H3K27me3 domains in growing oocytes but dissociates from chromatin in fully grown oocytes. After fertilization, PRC2 rebinds noncanonical H3K27me3 domains before relocating to Polycomb targets in blastocysts. Interestingly, the binding and activity of PRC2 are restricted by a maternal inhibitory factor, EZH inhibitory protein (EZHIP), which co-binds with PRC2. Upon knockout of Ezhip, hyperactive PRC2 promiscuously deposits H3K27me3 genome-wide. This overwrites H3K27me3 memories at noncanonical imprinted genes and paradoxically causes derepression of H3K27me3 targets, defective X chromosome inactivation, and diluted chromatin PRC2. H3K27me3 restoration at Polycomb targets after implantation is also attenuated, accompanied by sub-lethality. These data unveil principles of epigenetic inheritance that both insufficient and excessive heterochromatic marks cause loss of epigenetic memories and repression.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"25 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1016/j.stem.2025.09.008
Ying Jing, Huifen Lu, Jingyi Li, Zan He, Liyun Zhao, Chen Zhang, Ziqi Huang, Lixiao Liu, Shuhui Sun, Shuai Ma, Concepcion Rodriguez Esteban, Xiaobing Fu, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Si Wang, Guang-Hui Liu
Ovarian aging plays a pivotal role in female reproductive health, with implications for treatment strategies and quality of life. However, the potential of a single pharmaceutical agent to mitigate primate ovarian aging remains largely unexplored. Our 3.3-year study in monkeys demonstrates that oral vitamin C has geroprotective effects against ovarian aging. Vitamin C diminishes key aging biomarkers, including oxidative stress and follicular depletion. Using a single-cell transcriptomic clock, we show that vitamin C can reduce the biological age of oocytes by 1.35 years and somatic cells by 5.66 years. This effect is partly mediated by the NRF2 pathway, which alleviates ovarian cell senescence and inflammation. Our findings highlight the role of vitamin C in combating primate ovarian aging and provide insights for developing interventions against human ovarian aging.
{"title":"Vitamin C conveys geroprotection on primate ovaries","authors":"Ying Jing, Huifen Lu, Jingyi Li, Zan He, Liyun Zhao, Chen Zhang, Ziqi Huang, Lixiao Liu, Shuhui Sun, Shuai Ma, Concepcion Rodriguez Esteban, Xiaobing Fu, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Si Wang, Guang-Hui Liu","doi":"10.1016/j.stem.2025.09.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.008","url":null,"abstract":"Ovarian aging plays a pivotal role in female reproductive health, with implications for treatment strategies and quality of life. However, the potential of a single pharmaceutical agent to mitigate primate ovarian aging remains largely unexplored. Our 3.3-year study in monkeys demonstrates that oral vitamin C has geroprotective effects against ovarian aging. Vitamin C diminishes key aging biomarkers, including oxidative stress and follicular depletion. Using a single-cell transcriptomic clock, we show that vitamin C can reduce the biological age of oocytes by 1.35 years and somatic cells by 5.66 years. This effect is partly mediated by the NRF2 pathway, which alleviates ovarian cell senescence and inflammation. Our findings highlight the role of vitamin C in combating primate ovarian aging and provide insights for developing interventions against human ovarian aging.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"54 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-13DOI: 10.1016/j.stem.2025.09.006
Riccardo De Santis, Laurent Jutras-Dubé, Sophia Bourdrel, Eleni Rice, Francesco M. Piccolo, Ali H. Brivanlou
The spatiotemporal regulation of morphogenetic signals, along with local tissue mechanics, guides morphogenesis and determines the shape of the embryo. However, how these signals integrate into developmental circuits remains poorly understood. Here, we developed a light-inducible strategy to induce BMP4 signaling with precise spatial coordinates in human pluripotent stem cells. Light-controlled BMP4 induces SMAD1–5 phosphorylation, resulting in amnion differentiation, and relies on a tension-dependent induction of WNT and NODAL for mesoderm differentiation. In response to BMP4 signaling, the mechanosensitive transcription factor YAP1 accumulates in the nucleus, where it represses WNT3 mRNA, regulating the induction of the three germ layers. Based on these findings, we developed a mathematical model that integrates tissue mechanics into morphogen dynamics, quantitatively explaining tissue-scale responses to BMP4 signaling. Thus, light induction of the morphogen BMP4 in human stem cell models elucidated the interplay between tissue mechanics and signaling at the onset of gastrulation.
{"title":"Crosstalk between tissue mechanics and BMP4 signaling regulates symmetry breaking in human gastrula models","authors":"Riccardo De Santis, Laurent Jutras-Dubé, Sophia Bourdrel, Eleni Rice, Francesco M. Piccolo, Ali H. Brivanlou","doi":"10.1016/j.stem.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.006","url":null,"abstract":"The spatiotemporal regulation of morphogenetic signals, along with local tissue mechanics, guides morphogenesis and determines the shape of the embryo. However, how these signals integrate into developmental circuits remains poorly understood. Here, we developed a light-inducible strategy to induce BMP4 signaling with precise spatial coordinates in human pluripotent stem cells. Light-controlled BMP4 induces SMAD1–5 phosphorylation, resulting in amnion differentiation, and relies on a tension-dependent induction of WNT and NODAL for mesoderm differentiation. In response to BMP4 signaling, the mechanosensitive transcription factor YAP1 accumulates in the nucleus, where it represses WNT3 mRNA, regulating the induction of the three germ layers. Based on these findings, we developed a mathematical model that integrates tissue mechanics into morphogen dynamics, quantitatively explaining tissue-scale responses to BMP4 signaling. Thus, light induction of the morphogen BMP4 in human stem cell models elucidated the interplay between tissue mechanics and signaling at the onset of gastrulation.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"9 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.stem.2025.09.007
Ziqi Dong, Niek Wit, Aastha Agarwal, Adam James Reid, Dnyanesh Dubal, Sina Beier, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Jelle van den Ameele, James A. Nathan, Emma L. Rawlins
Human lungs experience dynamic oxygen tension during development. Here, we show that hypoxia directly regulates human lung epithelial cell identity using tissue-derived organoids. Fetal multipotent lung epithelial progenitors remain undifferentiated in a self-renewing culture condition under normoxia but spontaneously differentiate toward multiple airway cell types and inhibit alveolar differentiation under hypoxia. Using chemical and genetic tools, we demonstrate that hypoxia-induced airway differentiation depends on hypoxia-inducible factor (HIF) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. KLF4 and KLF5 are direct HIF targets that promote basal and secretory cell fates. Moreover, hypoxia is sufficient to convert alveolar type 2 cells derived from both human fetal and adult lungs to airway cells, including aberrant basal-like cells that exist in human fibrotic lungs. These findings reveal roles for hypoxia and HIF activity in the developing human lung epithelium and have implications for aberrant cell fate changes in pathological lungs.
{"title":"Hypoxia promotes airway differentiation in the human lung epithelium","authors":"Ziqi Dong, Niek Wit, Aastha Agarwal, Adam James Reid, Dnyanesh Dubal, Sina Beier, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Jelle van den Ameele, James A. Nathan, Emma L. Rawlins","doi":"10.1016/j.stem.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.007","url":null,"abstract":"Human lungs experience dynamic oxygen tension during development. Here, we show that hypoxia directly regulates human lung epithelial cell identity using tissue-derived organoids. Fetal multipotent lung epithelial progenitors remain undifferentiated in a self-renewing culture condition under normoxia but spontaneously differentiate toward multiple airway cell types and inhibit alveolar differentiation under hypoxia. Using chemical and genetic tools, we demonstrate that hypoxia-induced airway differentiation depends on hypoxia-inducible factor (HIF) activity, with HIF1α and HIF2α differentially regulating progenitor fate decisions. KLF4 and KLF5 are direct HIF targets that promote basal and secretory cell fates. Moreover, hypoxia is sufficient to convert alveolar type 2 cells derived from both human fetal and adult lungs to airway cells, including aberrant basal-like cells that exist in human fibrotic lungs. These findings reveal roles for hypoxia and HIF activity in the developing human lung epithelium and have implications for aberrant cell fate changes in pathological lungs.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"109 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.stem.2025.08.008
Kevin M. Waters, Akil Merchant, De-Chen Lin
Chan et al.1 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.
{"title":"Unmasking cancer’s hidden nerve route with patient-derived organoids","authors":"Kevin M. Waters, Akil Merchant, De-Chen Lin","doi":"10.1016/j.stem.2025.08.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.008","url":null,"abstract":"Chan et al.<span><span><sup>1</sup></span></span> 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.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"10 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.stem.2025.09.005
Giorgia Tosoni, Evgenia Salta
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.
{"title":"Mind, mood and new neurons: Probing adult hippocampal neurogenesis in neuropsychiatry and beyond","authors":"Giorgia Tosoni, Evgenia Salta","doi":"10.1016/j.stem.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.005","url":null,"abstract":"In this issue of <em>Cell Stem Cell</em>, Márquez-Valadez, Gallardo-Caballero, and Llorens-Martín<span><span><sup>1</sup></span></span> 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.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"9 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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. Finally, as humanity prepares for long-duration lunar and Martian missions, space-based stem cell research offers transformative biomedical applications but also raises new technical, regulatory, workforce development, and ethical challenges.
{"title":"Stem cell research in space: Advancing regenerative medicine beyond Earth","authors":"Maedeh Mozneb, Madelyn Arzt, Jemima Moses, Sean Escopete, Lauren Wiegand, Arun Sharma","doi":"10.1016/j.stem.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.001","url":null,"abstract":"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. Finally, as humanity prepares for long-duration lunar and Martian missions, space-based stem cell research offers transformative biomedical applications but also raises new technical, regulatory, workforce development, and ethical challenges.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"157 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.stem.2025.09.002
The generation of stem-cell-based embryo models has ushered in a new era for human embryology, but improving their reproducibility and lineage fidelit…
基于干细胞的胚胎模型的产生为人类胚胎学开辟了一个新时代，但提高它们的可重复性和谱系保真度…
{"title":"Raising the bar for human post-implantation embryo models","authors":"","doi":"10.1016/j.stem.2025.09.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.002","url":null,"abstract":"The generation of stem-cell-based embryo models has ushered in a new era for human embryology, but improving their reproducibility and lineage fidelit…","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"18 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.stem.2025.08.016
Zekun Wu, Hongan Ren, Leqian Yu
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.
{"title":"Building the start: Unlocking advanced stem cell-based embryo models","authors":"Zekun Wu, Hongan Ren, Leqian Yu","doi":"10.1016/j.stem.2025.08.016","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.016","url":null,"abstract":"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.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"114 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.stem.2025.09.004
Muzhen Qiao, Peng Jiang
Recent studies highlight microglial replacement as a promising therapeutic approach for neurological disease. Wu et al.1 demonstrated that transplanted bone marrow-derived cells halted ALSP progression, while Mader et al.2 introduced a strategy that avoids systemic bone marrow ablation toxicity and reduces immune rejection, collectively validating this strategy’s therapeutic potential.
{"title":"From sentinels to engineers: The future of microglia in brain regeneration","authors":"Muzhen Qiao, Peng Jiang","doi":"10.1016/j.stem.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.09.004","url":null,"abstract":"Recent studies highlight microglial replacement as a promising therapeutic approach for neurological disease. Wu et al.<span><span><sup>1</sup></span></span> demonstrated that transplanted bone marrow-derived cells halted ALSP progression, while Mader et al.<span><span><sup>2</sup></span></span> introduced a strategy that avoids systemic bone marrow ablation toxicity and reduces immune rejection, collectively validating this strategy’s therapeutic potential.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"7 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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