Pub Date : 2025-09-15DOI: 10.1016/j.stem.2025.08.010
Berenice Márquez-Valadez, Marta Gallardo-Caballero, María Llorens-Martín
Adult hippocampal neurogenesis (AHN) regulates hippocampal-dependent functions and is targeted by physiological aging and neurodegenerative conditions. Patients with neuropsychiatric disorders show hippocampal abnormalities that might be related to changes in AHN. Here, we sought to determine whether major depression, schizophrenia, and bipolar disorder threaten the integrity of human AHN and the homeostasis of the dentate gyrus (DG) neurogenic niche—a specialized microenvironment in which new neurons grow. Our results show that the initial and intermediate stages of AHN, as well as distinct components of the niche, are selectively affected in these disorders. Demographics and various lifestyle-related factors (such as the consumption of alcohol and drugs of abuse) modulate both AHN and the cells that compose the niche, not only in patients with these disorders but also in neurologically healthy control individuals. These data might be relevant for the design of future strategies to treat and prevent mental health conditions.
{"title":"Human adult hippocampal neurogenesis is shaped by neuropsychiatric disorders, demographics, and lifestyle-related factors","authors":"Berenice Márquez-Valadez, Marta Gallardo-Caballero, María Llorens-Martín","doi":"10.1016/j.stem.2025.08.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.010","url":null,"abstract":"Adult hippocampal neurogenesis (AHN) regulates hippocampal-dependent functions and is targeted by physiological aging and neurodegenerative conditions. Patients with neuropsychiatric disorders show hippocampal abnormalities that might be related to changes in AHN. Here, we sought to determine whether major depression, schizophrenia, and bipolar disorder threaten the integrity of human AHN and the homeostasis of the dentate gyrus (DG) neurogenic niche—a specialized microenvironment in which new neurons grow. Our results show that the initial and intermediate stages of AHN, as well as distinct components of the niche, are selectively affected in these disorders. Demographics and various lifestyle-related factors (such as the consumption of alcohol and drugs of abuse) modulate both AHN and the cells that compose the niche, not only in patients with these disorders but also in neurologically healthy control individuals. These data might be relevant for the design of future strategies to treat and prevent mental health conditions.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"101 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059696","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 : 2025-09-05DOI: 10.1016/j.stem.2025.08.014
Clive N. Svendsen
Section snippets
Declaration of interests
C.N.S. serves on the advisory board of Cell Stem Cell.
部分片段利益声明担任Cell Stem Cell的顾问委员会成员。
{"title":"Adopting novel alternative methods (NAMs) for biomedical research—What is the right approach?","authors":"Clive N. Svendsen","doi":"10.1016/j.stem.2025.08.014","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.014","url":null,"abstract":"<h2>Section snippets</h2><section><section></section></section><section><section><h2>Declaration of interests</h2>C.N.S. serves on the advisory board of <em>Cell Stem Cell</em>.</section></section>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"23 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996041","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 : 2025-09-04DOI: 10.1016/j.stem.2025.08.004
Vladyslav Bondarenko, Margherita Yayoi Turco
Stem cells and organoids enable the modeling of various aspects of human development in vitro, yet integrating them to study maternal-fetal interactions remains challenging. In this review, we explore the current in vitro models of the endometrium, placenta, and embryo and identify key challenges associated with their integration, including the establishment of morpho-functional complexity, spatiotemporal coordination, and appropriate in vivo benchmarking. We propose an interdisciplinary perspective that emphasizes a shift from “building blocks” to “building interactions.” Altogether, we provide a discussion on the challenges and prospects for advancing mechanistic understanding of intrauterine human development and the maternal-fetal interface.
{"title":"Modeling the human maternal-fetal interface","authors":"Vladyslav Bondarenko, Margherita Yayoi Turco","doi":"10.1016/j.stem.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.004","url":null,"abstract":"Stem cells and organoids enable the modeling of various aspects of human development <em>in vitro</em>, yet integrating them to study maternal-fetal interactions remains challenging. In this review, we explore the current <em>in vitro</em> models of the endometrium, placenta, and embryo and identify key challenges associated with their integration, including the establishment of morpho-functional complexity, spatiotemporal coordination, and appropriate <em>in vivo</em> benchmarking. We propose an interdisciplinary perspective that emphasizes a shift from “building blocks” to “building interactions.” Altogether, we provide a discussion on the challenges and prospects for advancing mechanistic understanding of intrauterine human development and the maternal-fetal interface.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"304 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987603","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 : 2025-09-04DOI: 10.1016/j.stem.2025.08.002
Longwei Liu, Yingxiao Wang
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,1 opening new opportunities for treating fibrotic diseases with precision immunotherapy.
{"title":"Severing the scar supply line: CAR-T in chronic kidney disease","authors":"Longwei Liu, Yingxiao Wang","doi":"10.1016/j.stem.2025.08.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.002","url":null,"abstract":"CAR-T cell therapy is rapidly being extended to target various pathophysiological processes beyond cancer. In this issue of <em>Cell Stem Cell</em>, Zhao et al. engineered PDGFRβ-specific CAR-T cells <em>in vivo</em> to selectively target extracellular matrix-producing cells in kidney fibrosis,<span><span><sup>1</sup></span></span> opening new opportunities for treating fibrotic diseases with precision immunotherapy.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"29 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987695","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 : 2025-09-04DOI: 10.1016/j.stem.2025.08.001
Jia Zhao, Shenghui Liang, Timothy J. Kieffer
While current stem cell differentiation protocols generate β cell-enriched islets that reverse hyperglycemia post-implantation, they can cause hypoglycemia. Meng et al.1 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.
{"title":"From β soloist to endocrine symphony: Subtype-complete islets conduct glucose harmony","authors":"Jia Zhao, Shenghui Liang, Timothy J. Kieffer","doi":"10.1016/j.stem.2025.08.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.001","url":null,"abstract":"While current stem cell differentiation protocols generate β cell-enriched islets that reverse hyperglycemia post-implantation, they can cause hypoglycemia. Meng et al.<span><span><sup>1</sup></span></span> 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.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"104 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987599","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 : 2025-09-04DOI: 10.1016/j.stem.2025.07.013
Jessica Pham, Jane Isquith, Larisa Balaian, Shuvro P. Nandi, Claire Engstrom, Karla Mack, Inge van der Werf, Patrick Chang, Jana Stoudemire, Luisa Ladel, Emma Klacking, Antonio Ruiz, Daisy Chilin-Fuentes, Jenna Sneifer, David Mays, Paul Gamble, Shelby Giza, Jiya Janowitz, Trevor Nienaber, Tejaswini Mishra, Catriona H.M. Jamieson
Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.
{"title":"Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging","authors":"Jessica Pham, Jane Isquith, Larisa Balaian, Shuvro P. Nandi, Claire Engstrom, Karla Mack, Inge van der Werf, Patrick Chang, Jana Stoudemire, Luisa Ladel, Emma Klacking, Antonio Ruiz, Daisy Chilin-Fuentes, Jenna Sneifer, David Mays, Paul Gamble, Shelby Giza, Jiya Janowitz, Trevor Nienaber, Tejaswini Mishra, Catriona H.M. Jamieson","doi":"10.1016/j.stem.2025.07.013","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.013","url":null,"abstract":"Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"35 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987604","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 : 2025-09-04DOI: 10.1016/j.stem.2025.08.003
Jung-Won Shin, Maksim V. Plikus
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.1 report that skin fat, notable for its ability to rapidly expand, harbors molecularly distinct precursors, primed for proliferation and differentiation into mature adipocytes.
{"title":"Ready, set, but no go: Skin fat comes preloaded with waiting precursors","authors":"Jung-Won Shin, Maksim V. Plikus","doi":"10.1016/j.stem.2025.08.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.003","url":null,"abstract":"Fat depots across the body dynamically tune their sizes in response to nutrient demands and nonmetabolic cues. Writing in <em>Cell Stem Cell</em>, Rivera-Gonzalez et al.<span><span><sup>1</sup></span></span> report that skin fat, notable for its ability to rapidly expand, harbors molecularly distinct precursors, primed for proliferation and differentiation into mature adipocytes.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"15 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987602","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 : 2025-09-04DOI: 10.1016/j.stem.2025.08.007
Rossella Ventura
Dysfunction of A10 midbrain dopaminergic (mDA) neurons is linked to psychiatric disorders, such as depression. In this issue, Yan et al.1 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.
{"title":"Engineered VTA dopaminergic neurons offer a new path to treating depression","authors":"Rossella Ventura","doi":"10.1016/j.stem.2025.08.007","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.007","url":null,"abstract":"Dysfunction of A10 midbrain dopaminergic (mDA) neurons is linked to psychiatric disorders, such as depression. In this issue, Yan et al.<span><span><sup>1</sup></span></span> 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.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"33 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987601","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 : 2025-09-04DOI: 10.1016/j.stem.2025.08.009
Roberto Castro-Gutierrez, Qizhi Tang
As stem cell therapies make great strides in clinical trials, the challenge of immune rejection has come into a sharper focus. Several recent clinical reports provide insight into the challenges posed by HLA mismatch and immunosuppression. Immunological analyses accompanying recent cell therapy trials suggest strategies that may mitigate these risks.
{"title":"Face off: Stem cell therapy versus the immune system","authors":"Roberto Castro-Gutierrez, Qizhi Tang","doi":"10.1016/j.stem.2025.08.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.009","url":null,"abstract":"As stem cell therapies make great strides in clinical trials, the challenge of immune rejection has come into a sharper focus. Several recent clinical reports provide insight into the challenges posed by HLA mismatch and immunosuppression. Immunological analyses accompanying recent cell therapy trials suggest strategies that may mitigate these risks.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"16 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987608","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 : 2025-09-02DOI: 10.1016/j.stem.2025.08.006
Becky K.C. Chan, Chu Zhang, Chi Him Poon, Marie H.Y. Lee, Hoi Yee Chu, Bei Wang, Sin-Guang Chen, Helen H.N. Yan, Suet Yi Leung, Alan S.L. Wong
The discrepancy between organoid and immortalized cell line cultures for cancer target discovery remains unclear. Here, our multi-tiered clustered regularly interspaced short palindromic repeats (CRISPR) screens reveal in vivo-relevant metabolic dependencies and synthetic lethal pairs that can be uncovered with tumor organoids but not cell lines or even three-dimensional (3D) spheroids. These screens identify lanosterol synthase and acetyl-coenzyme A (CoA) carboxylase inhibitors as effective treatments that impede xenografted tumor growth in mice. These lipid metabolic inhibitors exhibit nanomolar half-maximal inhibitory concentration (IC50) values across diverse human gastric cancer organoids resistant to first-line treatments. Mechanistically, gastric cancer organoids and in vivo tumors exhibit lipid metabolic adaptations not seen in two-dimensional (2D) in vitro cultures. Additionally, enteric neurons modulate lipid metabolism in tumor organoids, altering drug sensitivity by up to two orders of magnitude. A neuron-cocultured CRISPR screen further reveals that acetyl-CoA carboxylase expression determines lanosterol synthase inhibitor efficacy. These findings highlight the critical roles of organoid environment and neuronal interaction in cancer lipid reliance.
{"title":"A combined enteric neuron-gastric tumor organoid reveals metabolic vulnerabilities in gastric cancer","authors":"Becky K.C. Chan, Chu Zhang, Chi Him Poon, Marie H.Y. Lee, Hoi Yee Chu, Bei Wang, Sin-Guang Chen, Helen H.N. Yan, Suet Yi Leung, Alan S.L. Wong","doi":"10.1016/j.stem.2025.08.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.006","url":null,"abstract":"The discrepancy between organoid and immortalized cell line cultures for cancer target discovery remains unclear. Here, our multi-tiered clustered regularly interspaced short palindromic repeats (CRISPR) screens reveal <em>in vivo</em>-relevant metabolic dependencies and synthetic lethal pairs that can be uncovered with tumor organoids but not cell lines or even three-dimensional (3D) spheroids. These screens identify lanosterol synthase and acetyl-coenzyme A (CoA) carboxylase inhibitors as effective treatments that impede xenografted tumor growth in mice. These lipid metabolic inhibitors exhibit nanomolar half-maximal inhibitory concentration (IC<sub>50</sub>) values across diverse human gastric cancer organoids resistant to first-line treatments. Mechanistically, gastric cancer organoids and <em>in vivo</em> tumors exhibit lipid metabolic adaptations not seen in two-dimensional (2D) <em>in vitro</em> cultures. Additionally, enteric neurons modulate lipid metabolism in tumor organoids, altering drug sensitivity by up to two orders of magnitude. A neuron-cocultured CRISPR screen further reveals that acetyl-CoA carboxylase expression determines lanosterol synthase inhibitor efficacy. These findings highlight the critical roles of organoid environment and neuronal interaction in cancer lipid reliance.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"31 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928463","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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