Pub Date : 2025-04-09DOI: 10.1016/j.stem.2025.03.008
Chiara Pavan, Kathryn C. Davidson, Natalie Payne, Stefano Frausin, Cameron P.J. Hunt, Niamh Moriarty, Miguel Á. Berrocal Rubio, Zahra Elahi, Andrew T. Quattrocchi, Kwaku Dad Abu-Bonsrah, Le Wang, William Clow, Huijuan Yang, Marc Pellegrini, Christine A. Wells, Lachlan H. Thompson, Andras Nagy, Clare L. Parish
Human pluripotent stem cell (hPSC)-derived therapies are a realistic possibility for numerous disorders, including Parkinson’s disease. While generating replacement neurons is achievable, immunosuppressive drug challenges, to prevent rejection, remain. Here we adopted a hPSC line (termed H1-FS-8IM), engineered to overexpress 8 immunomodulatory transgenes, to enable transplant immune evasion. In co-cultures, H1-FS-8IM PSC-derived midbrain neurons evaded rejection by T lymphocytes, natural killer cells, macrophages, and dendritic cells. In humanized mice, allogeneic H1-FS-8IM neural grafts evaded rejection, while control hPSC-derived neural grafts evoked activation of human immune cells, elevated inflammatory cytokines in blood and cerebrospinal fluid, and caused spleen and lymph node enlargement. H1-FS-8IM neural grafts retained functionality, reversing motor deficits in Parkinsonian rats. Additional incorporation of a suicide gene into the H1-FS-8IM hPSC line enabled proliferative cell elimination within grafts. Findings demonstrate feasibility of generating a population-wide applicable, safe, off-the-shelf cell product, suitable for treating diseases for which cell-based therapies are a viable option.
{"title":"A cloaked human stem-cell-derived neural graft capable of functional integration and immune evasion in rodent models","authors":"Chiara Pavan, Kathryn C. Davidson, Natalie Payne, Stefano Frausin, Cameron P.J. Hunt, Niamh Moriarty, Miguel Á. Berrocal Rubio, Zahra Elahi, Andrew T. Quattrocchi, Kwaku Dad Abu-Bonsrah, Le Wang, William Clow, Huijuan Yang, Marc Pellegrini, Christine A. Wells, Lachlan H. Thompson, Andras Nagy, Clare L. Parish","doi":"10.1016/j.stem.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.008","url":null,"abstract":"Human pluripotent stem cell (hPSC)-derived therapies are a realistic possibility for numerous disorders, including Parkinson’s disease. While generating replacement neurons is achievable, immunosuppressive drug challenges, to prevent rejection, remain. Here we adopted a hPSC line (termed H1-FS-8IM), engineered to overexpress 8 immunomodulatory transgenes, to enable transplant immune evasion. In co-cultures, H1-FS-8IM PSC-derived midbrain neurons evaded rejection by T lymphocytes, natural killer cells, macrophages, and dendritic cells. In humanized mice, allogeneic H1-FS-8IM neural grafts evaded rejection, while control hPSC-derived neural grafts evoked activation of human immune cells, elevated inflammatory cytokines in blood and cerebrospinal fluid, and caused spleen and lymph node enlargement. H1-FS-8IM neural grafts retained functionality, reversing motor deficits in Parkinsonian rats. Additional incorporation of a suicide gene into the H1-FS-8IM hPSC line enabled proliferative cell elimination within grafts. Findings demonstrate feasibility of generating a population-wide applicable, safe, off-the-shelf cell product, suitable for treating diseases for which cell-based therapies are a viable option.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"43 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806109","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}
Enterocytes and four classic secretory cell types derive from intestinal epithelial stem cells. Based on morphology, location, and canonical markers, goblet and Paneth cells are considered distinct secretory types. Here, we report high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of their enteroendocrine or tuft cell siblings. Mouse and human goblet and Paneth cells express extraordinary fractions of few antimicrobial genes, which reflect specific responses to local niches. Wnt signaling retains some ATOH1+ secretory cells in crypt bottoms, where the absence of BMP signaling potently induces Paneth features. Cells that migrate away from crypt bottoms encounter BMPs and thereby acquire goblet properties. These phenotypes and underlying accessible cis-elements interconvert in post-mitotic cells. Thus, goblet and Paneth properties represent alternative phenotypic manifestations of a common signal-responsive terminal cell type. These findings reveal exquisite niche-dependent cell plasticity and cis-regulatory dynamics in likely response to antimicrobial needs.
{"title":"Intestinal secretory differentiation reflects niche-driven phenotypic and epigenetic plasticity of a common signal-responsive terminal cell","authors":"Swarnabh Bhattacharya, Guodong Tie, Pratik N.P. Singh, Ermanno Malagola, Onur Eskiocak, Ruiyang He, Judith Kraiczy, Wei Gu, Yakov Perlov, Aybuke Alici-Garipcan, Semir Beyaz, Timothy C. Wang, Qiao Zhou, Ramesh A. Shivdasani","doi":"10.1016/j.stem.2025.03.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.005","url":null,"abstract":"Enterocytes and four classic secretory cell types derive from intestinal epithelial stem cells. Based on morphology, location, and canonical markers, goblet and Paneth cells are considered distinct secretory types. Here, we report high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of their enteroendocrine or tuft cell siblings. Mouse and human goblet and Paneth cells express extraordinary fractions of few antimicrobial genes, which reflect specific responses to local niches. Wnt signaling retains some ATOH1<sup>+</sup> secretory cells in crypt bottoms, where the absence of BMP signaling potently induces Paneth features. Cells that migrate away from crypt bottoms encounter BMPs and thereby acquire goblet properties. These phenotypes and underlying accessible <em>cis</em>-elements interconvert in post-mitotic cells. Thus, goblet and Paneth properties represent alternative phenotypic manifestations of a common signal-responsive terminal cell type. These findings reveal exquisite niche-dependent cell plasticity and <em>cis</em>-regulatory dynamics in likely response to antimicrobial needs.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"59 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797998","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 : 2025-04-03DOI: 10.1016/j.stem.2025.02.012
Alain van Mil, Jasmijn Janssen, Eva van Rooij
Researchers have demonstrated that a stem cell-derived heart muscle patch can safely remuscularize failing hearts.1 Published in Nature, the study shows successful long-term cardiac integration of a patch in a primate model and a human patient with no adverse effects. This breakthrough marks a major step toward regenerative therapies for advanced heart failure.
{"title":"Engineered heart tissue patches: A milestone in cardiac regenerative medicine","authors":"Alain van Mil, Jasmijn Janssen, Eva van Rooij","doi":"10.1016/j.stem.2025.02.012","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.012","url":null,"abstract":"Researchers have demonstrated that a stem cell-derived heart muscle patch can safely remuscularize failing hearts.<span><span><sup>1</sup></span></span> Published in <em>Nature</em>, the study shows successful long-term cardiac integration of a patch in a primate model and a human patient with no adverse effects. This breakthrough marks a major step toward regenerative therapies for advanced heart failure.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"26 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766844","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 : 2025-04-03DOI: 10.1016/j.stem.2025.03.004
Tobias Deuse, Sonja Schrepfer
The new era of cell therapeutics has started with autologous products to avoid immune rejection. However, therapeutics derived from allogeneic cells could be scaled and made available for a much larger patient population if immune rejection could reliably be overcome. In this review, we outline gene engineering concepts aimed at generating immune-evasive cells. First, we summarize the current state of allogeneic immune cell therapies, and second, we compile the still limited data for allogeneic cell replacement therapies. We emphasize the advances in this fast-developing field and provide an optimistic outlook for future allogeneic cell therapies.
{"title":"Progress and challenges in developing allogeneic cell therapies","authors":"Tobias Deuse, Sonja Schrepfer","doi":"10.1016/j.stem.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.004","url":null,"abstract":"The new era of cell therapeutics has started with autologous products to avoid immune rejection. However, therapeutics derived from allogeneic cells could be scaled and made available for a much larger patient population if immune rejection could reliably be overcome. In this review, we outline gene engineering concepts aimed at generating immune-evasive cells. First, we summarize the current state of allogeneic immune cell therapies, and second, we compile the still limited data for allogeneic cell replacement therapies. We emphasize the advances in this fast-developing field and provide an optimistic outlook for future allogeneic cell therapies.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"107 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766845","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 : 2025-04-03DOI: 10.1016/j.stem.2025.03.001
Eirini P. Papapetrou
Rodriguez-Fraticelli and colleagues combine genetic barcoding with ex vivo expansion and sister-cell analysis of murine hematopoietic stem cells (HSCs) carrying inducible leukemia driver mutations. This approach allows them to capture the intrinsic heterogeneity of clonal cell behaviors and study how these impact cell fates upon acquisition of leukemia driver mutations.
{"title":"The clones have STRACK: Tracing responses to leukemic mutations","authors":"Eirini P. Papapetrou","doi":"10.1016/j.stem.2025.03.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.001","url":null,"abstract":"Rodriguez-Fraticelli and colleagues combine genetic barcoding with <em>ex vivo</em> expansion and sister-cell analysis of murine hematopoietic stem cells (HSCs) carrying inducible leukemia driver mutations. This approach allows them to capture the intrinsic heterogeneity of clonal cell behaviors and study how these impact cell fates upon acquisition of leukemia driver mutations.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"37 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766843","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 : 2025-04-03DOI: 10.1016/j.stem.2025.03.003
Nissim Benvenisty, Jonathan S. Draper, Paul J. Gokhale, Lyn Healy, Zoe Hewitt, Deborah Hursh, Adam Hodgson, Tenneille E. Ludwig, Nancy Mah, Sarah E. McClelland, Milena Mennecozzi, Florian T. Merkle, Joanne C. Mountford, Martin Pera, Alessandro Prigione, Tristan A. Rodriguez, Andrea Rossi, Foad J. Rouhani, Kourosh Saeb-Parsy, Lucia Selfa Aspiroz, Ivana Barbaric
Human pluripotent stem cell (hPSC)-based therapies offer promise but pose potential risks due to culture-acquired genetic variants, some of which have been linked with cancer. An international workshop addressed these concerns, highlighting the need for improved strategies to stratify variants and chart a path toward definitive guidelines in hPSC-based therapy.
{"title":"A call to action for deciphering genetic variants in human pluripotent stem cells for cell therapy","authors":"Nissim Benvenisty, Jonathan S. Draper, Paul J. Gokhale, Lyn Healy, Zoe Hewitt, Deborah Hursh, Adam Hodgson, Tenneille E. Ludwig, Nancy Mah, Sarah E. McClelland, Milena Mennecozzi, Florian T. Merkle, Joanne C. Mountford, Martin Pera, Alessandro Prigione, Tristan A. Rodriguez, Andrea Rossi, Foad J. Rouhani, Kourosh Saeb-Parsy, Lucia Selfa Aspiroz, Ivana Barbaric","doi":"10.1016/j.stem.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.003","url":null,"abstract":"Human pluripotent stem cell (hPSC)-based therapies offer promise but pose potential risks due to culture-acquired genetic variants, some of which have been linked with cancer. An international workshop addressed these concerns, highlighting the need for improved strategies to stratify variants and chart a path toward definitive guidelines in hPSC-based therapy.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"44 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766847","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 : 2025-04-03DOI: 10.1016/j.stem.2025.03.007
Petter Brodin
Wagoner et al.1 use human tonsil organoids to uncover key immune mechanisms driving influenza vaccine responses. They identify Th1 cell frequencies as a critical predictor of neutralizing antibody responses to inactivated vaccines, providing new insights into vaccine effectiveness and paving the way for more targeted vaccine development in the future.
{"title":"Tonsils weigh in on flu-specific immunity","authors":"Petter Brodin","doi":"10.1016/j.stem.2025.03.007","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.007","url":null,"abstract":"Wagoner et al.<span><span><sup>1</sup></span></span> use human tonsil organoids to uncover key immune mechanisms driving influenza vaccine responses. They identify Th1 cell frequencies as a critical predictor of neutralizing antibody responses to inactivated vaccines, providing new insights into vaccine effectiveness and paving the way for more targeted vaccine development in the future.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"58 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766842","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 : 2025-04-03DOI: 10.1016/j.stem.2025.02.014
Chiyeol Choi, Tae-Hee Kim
Human intestinal organoids (HIOs) generated from induced pluripotent stem cells (iPSCs) are utilized for disease modeling but they lack a full complement of niche components. Childs et al.1 demonstrate that EPIREGULIN-driven HIOs mature into functional, neuromuscular, and vascularized niches, establishing a powerful platform for human gut physiology and disease research.
{"title":"A robust ingredient makes human gut stem cell niches on a dish","authors":"Chiyeol Choi, Tae-Hee Kim","doi":"10.1016/j.stem.2025.02.014","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.014","url":null,"abstract":"Human intestinal organoids (HIOs) generated from induced pluripotent stem cells (iPSCs) are utilized for disease modeling but they lack a full complement of niche components. Childs et al.<span><span><sup>1</sup></span></span> demonstrate that EPIREGULIN-driven HIOs mature into functional, neuromuscular, and vascularized niches, establishing a powerful platform for human gut physiology and disease research.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"23 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766920","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 : 2025-03-31DOI: 10.1016/j.stem.2025.03.002
Colleen E. O’Connor, Fan Zhang, Anna Neufeld, Olivia Prado, Susana P. Simmonds, Chelsea L. Fortin, Fredrik Johansson, Jonathan Mene, Sarah H. Saxton, Irina Kopyeva, Nicole E. Gregorio, Zachary James, Cole A. DeForest, Elizabeth C. Wayne, Daniela M. Witten, Kelly R. Stevens
Human engineered tissues hold great promise for therapeutic tissue regeneration and repair. Yet, development of these technologies often stalls at the stage of in vivo studies due to the complexity of engineered tissue formulations, which are often composed of diverse cell populations and material elements, along with the tedious nature of in vivo experiments. We introduce a “plug and play” platform called parallelized host apposition for screening tissues in vivo (PHAST). PHAST enables parallelized in vivo testing of 43 three-dimensional microtissues in a single 3D-printed device. Using PHAST, we screen microtissue formations with varying cellular and material components and identify formulations that support vascular graft-host inosculation and engineered liver tissue function in vivo. Our studies reveal that the cellular population(s) that should be included in engineered tissues for optimal in vivo performance is material dependent. PHAST could thus accelerate development of human tissue therapies for clinical regeneration and repair.
{"title":"Bioprinted platform for parallelized screening of engineered microtissues in vivo","authors":"Colleen E. O’Connor, Fan Zhang, Anna Neufeld, Olivia Prado, Susana P. Simmonds, Chelsea L. Fortin, Fredrik Johansson, Jonathan Mene, Sarah H. Saxton, Irina Kopyeva, Nicole E. Gregorio, Zachary James, Cole A. DeForest, Elizabeth C. Wayne, Daniela M. Witten, Kelly R. Stevens","doi":"10.1016/j.stem.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.002","url":null,"abstract":"Human engineered tissues hold great promise for therapeutic tissue regeneration and repair. Yet, development of these technologies often stalls at the stage of <em>in vivo</em> studies due to the complexity of engineered tissue formulations, which are often composed of diverse cell populations and material elements, along with the tedious nature of <em>in vivo</em> experiments. We introduce a “plug and play” platform called parallelized host apposition for screening tissues <em>in vivo</em> (PHAST). PHAST enables parallelized <em>in vivo</em> testing of 43 three-dimensional microtissues in a single 3D-printed device. Using PHAST, we screen microtissue formations with varying cellular and material components and identify formulations that support vascular graft-host inosculation and engineered liver tissue function <em>in vivo</em>. Our studies reveal that the cellular population(s) that should be included in engineered tissues for optimal <em>in vivo</em> performance is material dependent. PHAST could thus accelerate development of human tissue therapies for clinical regeneration and repair.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"48 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737205","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}
Chronic stress adversely affects intestinal health, but the specific neural pathways linking the brain to intestinal tissue are not fully understood. Here, we show that chronic stress-induced activation of the central amygdala-dorsal motor nucleus of the vagus (CeA-DMV) pathway accelerates premature aging and impairs the stemness of intestinal stem cells (ISCs). This pathway influences ISC function independently of the microbiota, the hypothalamic-pituitary-adrenal (HPA) axis, the immune response, and the sympathetic nervous system (SNS). Under chronic stress, DMV-mediated vagal activation prompts cholinergic enteric neurons to release acetylcholine (ACh), which engages ISCs via the M3 muscarinic acetylcholine receptor (CHRM3). This interaction activates the p38 mitogen-activated protein kinase (MAPK) pathway, triggering growth arrest and mitochondrial fragmentation, thereby accelerating an aging-like decline in ISCs. Together, our findings provide insights into an alternative neural mechanism that links stress to intestinal dysfunction. Strategies targeting the DMV-associated vagal pathway represent potential therapeutic approaches for stress-induced intestinal diseases.
{"title":"Vagal pathway activation links chronic stress to decline in intestinal stem cell function","authors":"Guoying Zhang, Yannan Lian, Qingguo Li, Shudi Zhou, Lili Zhang, Liting Chen, Junzhe Tang, Hailong Liu, Ni Li, Qiang Pan, Yongqiang Gu, Naiheng Lin, Hanling Wang, Xuege Wang, Jiacheng Guo, Wei Zhang, Zige Jin, Beitao Xu, Xiao Su, Moubin Lin, Jun Qin","doi":"10.1016/j.stem.2025.02.016","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.016","url":null,"abstract":"Chronic stress adversely affects intestinal health, but the specific neural pathways linking the brain to intestinal tissue are not fully understood. Here, we show that chronic stress-induced activation of the central amygdala-dorsal motor nucleus of the vagus (CeA-DMV) pathway accelerates premature aging and impairs the stemness of intestinal stem cells (ISCs). This pathway influences ISC function independently of the microbiota, the hypothalamic-pituitary-adrenal (HPA) axis, the immune response, and the sympathetic nervous system (SNS). Under chronic stress, DMV-mediated vagal activation prompts cholinergic enteric neurons to release acetylcholine (ACh), which engages ISCs via the M3 muscarinic acetylcholine receptor (CHRM3). This interaction activates the p38 mitogen-activated protein kinase (MAPK) pathway, triggering growth arrest and mitochondrial fragmentation, thereby accelerating an aging-like decline in ISCs. Together, our findings provide insights into an alternative neural mechanism that links stress to intestinal dysfunction. Strategies targeting the DMV-associated vagal pathway represent potential therapeutic approaches for stress-induced intestinal diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"21 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666286","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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