Pub Date : 2025-07-17DOI: 10.1016/j.stem.2025.06.010
Infencia Xavier Raj, Won Kyun Koh, Jessica Harrison, Christine R. Zhang, Barbara Soares, Roberta Amato, Aishwarya Krishnan, David R. O’Leary, Hassan Bjeije, Tyler M. Parsons, Wentao Han, Andrew L. Young, Ting Wang, Luis F.Z. Batista, Grant A. Challen
DNMT3A is a critical regulator of hematopoietic stem cell (HSC) fate decisions and the most recurrently mutated gene in human clonal hematopoiesis (CH). DNMT3A is described as a DNA methyltransferase enzyme, but cells with DNMT3A loss of function show minor changes in DNA methylation that do not correlate with altered gene expression. To explore the possibility that Dnmt3a has DNA-methylation-independent functions in HSCs, we created an allelic series of mice with varying levels of DNA-methylation-impaired Dnmt3a. Clonal expansion of Dnmt3a-deficient HSCs was rescued by Dnmt3a proteins lacking DNA methylation capacity, suggesting that Dnmt3a has important non-canonical functions in HSCs. Dnmt3a-null HSCs can be transplanted indefinitely, implying the ability to circumvent mechanisms that limit the replicative lifespan of HSCs, such as telomere shortening. Dnmt3a-null HSCs show increased telomerase activity and sustain telomere length over serial transplantation, revealing a previously unidentified role for DNMT3A mutations in regulating HSC longevity that is unrelated to DNA methylation function.
{"title":"Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity","authors":"Infencia Xavier Raj, Won Kyun Koh, Jessica Harrison, Christine R. Zhang, Barbara Soares, Roberta Amato, Aishwarya Krishnan, David R. O’Leary, Hassan Bjeije, Tyler M. Parsons, Wentao Han, Andrew L. Young, Ting Wang, Luis F.Z. Batista, Grant A. Challen","doi":"10.1016/j.stem.2025.06.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.010","url":null,"abstract":"DNMT3A is a critical regulator of hematopoietic stem cell (HSC) fate decisions and the most recurrently mutated gene in human clonal hematopoiesis (CH). DNMT3A is described as a DNA methyltransferase enzyme, but cells with DNMT3A loss of function show minor changes in DNA methylation that do not correlate with altered gene expression. To explore the possibility that Dnmt3a has DNA-methylation-independent functions in HSCs, we created an allelic series of mice with varying levels of DNA-methylation-impaired Dnmt3a. Clonal expansion of <em>Dnmt3a</em>-deficient HSCs was rescued by Dnmt3a proteins lacking DNA methylation capacity, suggesting that Dnmt3a has important non-canonical functions in HSCs. <em>Dnmt3a</em>-null HSCs can be transplanted indefinitely, implying the ability to circumvent mechanisms that limit the replicative lifespan of HSCs, such as telomere shortening. <em>Dnmt3a</em>-null HSCs show increased telomerase activity and sustain telomere length over serial transplantation, revealing a previously unidentified role for <em>DNMT3A</em> mutations in regulating HSC longevity that is unrelated to DNA methylation function.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645285","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 : 2025-07-11DOI: 10.1016/j.stem.2025.06.009
Shawn Goyal, Cynthia X. Guo, Ojas Singh, Adrienne Ranger, Caitlin F. Harrigan, Justin Meade, Alexander Luchak, Derek K. Tsang, Herbert Y. Gaisano, Nan Gao, Scott A. Yuzwa, Jeffrey L. Wrana, Dana J. Philpott, Scott D. Gray-Owen, Stephen E. Girardin
ADP-heptose (ADP-Hep), a metabolite produced by gram-negative bacteria, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the function of ALPK1-TIFA signaling in primary cells and in physiological settings remains poorly understood. Here, we showed that, in the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the intestinal stem cell (ISC) pool, where they controlled the replacement of homeostatic ISCs by new revival stem cells (revSCs) following injury. Mechanistically, ADP-Hep triggered pro-inflammatory nuclear factor κB (NF-κB) signaling and tumor necrosis factor (TNF)-dependent ISC apoptosis, which initiated a transforming growth factor β (TGF-β)- and YAP-dependent revSC program. Single-cell transcriptomics and lineage-tracing experiments identified Paneth cells as a cell of origin for revSC induction in response to ADP-Hep. In vivo, revSC emergence following irradiation or dextran-sodium-sulfate-induced injury was blunted in Tifa−/− mice. Together, our work reveals that ALPK1-TIFA signaling contributes to ISC turnover in response to bacterial detection in the intestine.
{"title":"Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury","authors":"Shawn Goyal, Cynthia X. Guo, Ojas Singh, Adrienne Ranger, Caitlin F. Harrigan, Justin Meade, Alexander Luchak, Derek K. Tsang, Herbert Y. Gaisano, Nan Gao, Scott A. Yuzwa, Jeffrey L. Wrana, Dana J. Philpott, Scott D. Gray-Owen, Stephen E. Girardin","doi":"10.1016/j.stem.2025.06.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.009","url":null,"abstract":"ADP-heptose (ADP-Hep), a metabolite produced by gram-negative bacteria, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the function of ALPK1-TIFA signaling in primary cells and in physiological settings remains poorly understood. Here, we showed that, in the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the intestinal stem cell (ISC) pool, where they controlled the replacement of homeostatic ISCs by new revival stem cells (revSCs) following injury. Mechanistically, ADP-Hep triggered pro-inflammatory nuclear factor κB (NF-κB) signaling and tumor necrosis factor (TNF)-dependent ISC apoptosis, which initiated a transforming growth factor β (TGF-β)- and YAP-dependent revSC program. Single-cell transcriptomics and lineage-tracing experiments identified Paneth cells as a cell of origin for revSC induction in response to ADP-Hep. <em>In vivo</em>, revSC emergence following irradiation or dextran-sodium-sulfate-induced injury was blunted in <em>Tifa</em><sup>−/−</sup> mice. Together, our work reveals that ALPK1-TIFA signaling contributes to ISC turnover in response to bacterial detection in the intestine.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"21 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602853","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 : 2025-07-03DOI: 10.1016/j.stem.2025.06.003
Courtney M. Cowan, Eric M. Pietras
Hematopoietic stem cells (HSCs) with mutations that can cause clonal hematopoiesis of indeterminate potential (CHIP) accumulate during aging. Agarwal et al.1 demonstrate in Nature that intestinal barrier permeability increases with age and enables the microbial metabolite ADP-heptose to reach the bone marrow, thus driving the expansion of DNMT3A-mutant HSCs.
{"title":"From symbiote to bad neighbor: The intestinal microbiome as a driver of CHIP","authors":"Courtney M. Cowan, Eric M. Pietras","doi":"10.1016/j.stem.2025.06.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.003","url":null,"abstract":"Hematopoietic stem cells (HSCs) with mutations that can cause clonal hematopoiesis of indeterminate potential (CHIP) accumulate during aging. Agarwal et al.<span><span><sup>1</sup></span></span> demonstrate in <em>Nature</em> that intestinal barrier permeability increases with age and enables the microbial metabolite ADP-heptose to reach the bone marrow, thus driving the expansion of DNMT3A-mutant HSCs.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547569","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 : 2025-07-03DOI: 10.1016/j.stem.2025.06.005
Hidetaka Hara, Yi Wang
A recent study in Nature demonstrates that a gene-edited pig liver can function in a brain-dead human for short-term support. This highlights the potential of xenogeneic liver transplantation as bridge therapy and opens new directions in regenerative medicine and cross-species organ engineering.
{"title":"Beyond transplantation: Gene-edited pig liver supports function in a human host","authors":"Hidetaka Hara, Yi Wang","doi":"10.1016/j.stem.2025.06.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.005","url":null,"abstract":"A recent study in <em>Nature</em> demonstrates that a gene-edited pig liver can function in a brain-dead human for short-term support. This highlights the potential of xenogeneic liver transplantation as bridge therapy and opens new directions in regenerative medicine and cross-species organ engineering.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547567","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 : 2025-07-03DOI: 10.1016/j.stem.2025.06.001
Chao Zhang, Yun Xia
The fusion of distal nephron and ureteric bud represents a critical developmental milestone required for establishing a functional kidney plumbing system. In this issue of Cell Stem Cell, Shi et al.1 report a protocol for generating human kidney organoids with an integrated collecting system by recapitulating this key developmental fusion event.
{"title":"Toward building kidney organoids with plumbing: Fusion of nephron with ureteric bud","authors":"Chao Zhang, Yun Xia","doi":"10.1016/j.stem.2025.06.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.001","url":null,"abstract":"The fusion of distal nephron and ureteric bud represents a critical developmental milestone required for establishing a functional kidney plumbing system. In this issue of <em>Cell Stem Cell</em>, Shi et al.<span><span><sup>1</sup></span></span> report a protocol for generating human kidney organoids with an integrated collecting system by recapitulating this key developmental fusion event.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"35 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547566","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 : 2025-07-03DOI: 10.1016/j.stem.2025.06.008
Laura Volta, Chiara F. Magnani
Toxicity and immune evasion have hindered the success of CAR T cells in HER2-positive solid tumors. In this issue of Cell Stem Cell, Hosking et al. present an iPSC-derived CAR T cell product engineered for tumor-selective targeting, resistance to the immunosuppressive tumor microenvironment, enhanced persistence and trafficking, and mitigation of antigen escape.
{"title":"The future belongs to those who believe in multiplex CAR T engineering","authors":"Laura Volta, Chiara F. Magnani","doi":"10.1016/j.stem.2025.06.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.008","url":null,"abstract":"Toxicity and immune evasion have hindered the success of CAR T cells in HER2-positive solid tumors. In this issue of <em>Cell Stem Cell,</em> Hosking et al. present an iPSC-derived CAR T cell product engineered for tumor-selective targeting, resistance to the immunosuppressive tumor microenvironment, enhanced persistence and trafficking, and mitigation of antigen escape.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"28 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547568","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 : 2025-07-02DOI: 10.1016/j.stem.2025.06.006
Katie A. Matatall, Trisha K. Wathan, Minh Nguyen, Hu Chen, Alexandra McDonald, Guantong Qi, Julia A. Belk, Marcus A. Florez, Duy T. Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M. Buttigieg, Chih-wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E. Kennedy, Arushana A. Maknojia, Apoorva Thatavarty, Josaura V. Fernandez Sanchez, Hind Bouzid, Katherine Y. King
Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer’s disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.
{"title":"TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice","authors":"Katie A. Matatall, Trisha K. Wathan, Minh Nguyen, Hu Chen, Alexandra McDonald, Guantong Qi, Julia A. Belk, Marcus A. Florez, Duy T. Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M. Buttigieg, Chih-wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E. Kennedy, Arushana A. Maknojia, Apoorva Thatavarty, Josaura V. Fernandez Sanchez, Hind Bouzid, Katherine Y. King","doi":"10.1016/j.stem.2025.06.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.006","url":null,"abstract":"Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer’s disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"3 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533906","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 : 2025-06-24DOI: 10.1016/j.stem.2025.06.004
Thomas A. Rando, Anne Brunet, Margaret A. Goodell
As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.
{"title":"Hallmarks of stem cell aging","authors":"Thomas A. Rando, Anne Brunet, Margaret A. Goodell","doi":"10.1016/j.stem.2025.06.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.004","url":null,"abstract":"As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371171","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 : 2025-06-24DOI: 10.1016/j.stem.2025.06.002
J. Jeya Vandana, Jiajun Zhu, Alice Maria Giani, Tuo Zhang, Lauretta A. Lacko, Dongliang Leng, D. Leland Taylor, Brian N. Lee, Zhaowei Han, Tiancheng Jiao, Yuanhao Huang, Meiqi Zhao, Xinyi Liu, Angie Chi Nok Chong, Dongxiang Xue, Zihe Meng, Jenny Z. Xiang, Chendong Pan, Wei Wang, Ali Naji, Shuibing Chen
Traditional chemical screens have focused on a single assay per screen, making them labor intensive and costly. Here, we combined a chemical screen with single-cell RNA sequencing (scRNA-seq) to perform Chemical Perturb-seq (ChemPerturb-seq), enabling a systematic analysis of the molecular changes of human beta cells upon individual small molecule treatments. Using this platform, we performed an in vivo barcoded screen and discovered a small molecule cocktail, including beta-lipotropin 61-91, insulin growth factor-1, and prostaglandin E2, with which preconditioning human beta cells and primary islets significantly enhanced function and survival when transplanted subcutaneously to female, but not to male, mice. We identified two additional molecules, serotonin and histamine, that promote islet function when transplanted subcutaneously to male mice using ChemPerturb-seq. Such small molecule cocktails could be applied to improve the current FDA-approved islet transplantation procedure. Finally, we developed an artificial intelligence (AI)-powered website, ChemPerturbDB, which provides user-friendly open access analysis of the extensive ChemPerturb-seq dataset.
{"title":"ChemPerturb-seq screen identifies a small molecule cocktail enhancing human beta cell survival after subcutaneous transplantation","authors":"J. Jeya Vandana, Jiajun Zhu, Alice Maria Giani, Tuo Zhang, Lauretta A. Lacko, Dongliang Leng, D. Leland Taylor, Brian N. Lee, Zhaowei Han, Tiancheng Jiao, Yuanhao Huang, Meiqi Zhao, Xinyi Liu, Angie Chi Nok Chong, Dongxiang Xue, Zihe Meng, Jenny Z. Xiang, Chendong Pan, Wei Wang, Ali Naji, Shuibing Chen","doi":"10.1016/j.stem.2025.06.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.002","url":null,"abstract":"Traditional chemical screens have focused on a single assay per screen, making them labor intensive and costly. Here, we combined a chemical screen with single-cell RNA sequencing (scRNA-seq) to perform Chemical Perturb-seq (ChemPerturb-seq), enabling a systematic analysis of the molecular changes of human beta cells upon individual small molecule treatments. Using this platform, we performed an <em>in vivo</em> barcoded screen and discovered a small molecule cocktail, including beta-lipotropin 61-91, insulin growth factor-1, and prostaglandin E2, with which preconditioning human beta cells and primary islets significantly enhanced function and survival when transplanted subcutaneously to female, but not to male, mice. We identified two additional molecules, serotonin and histamine, that promote islet function when transplanted subcutaneously to male mice using ChemPerturb-seq. Such small molecule cocktails could be applied to improve the current FDA-approved islet transplantation procedure. Finally, we developed an artificial intelligence (AI)-powered website, ChemPerturbDB, which provides user-friendly open access analysis of the extensive ChemPerturb-seq dataset.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"26 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371170","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 : 2025-06-24DOI: 10.1016/j.stem.2025.05.015
Deepti Lall, Michael J. Workman, Samuel Sances, Briana N. Ondatje, Shaughn Bell, George Lawless, Amanda Woodbury, Dylan West, Amanda Meyer, Andrea Matlock, Vineet Vaibhav, Jennifer E. Van Eyk, Clive N. Svendsen
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder in which motor neurons (MNs) of the brain and spinal cord degenerate, leading to paralysis. Generating MNs from patient-specific induced pluripotent stem cells (iPSCs) may help elucidate early stages of disease. Here, we combined MNs from patients with early-onset disease with brain microvascular endothelial-like cells in a microfluidic device we termed spinal cord chips (SC-chips) and added media flow, which enhanced neuronal maturation and improved cellular health. Bulk transcriptomic and proteomic analyses of SC-chips revealed differences between control and ALS samples, including increased levels of neurofilaments. Single-nuclei RNA sequencing revealed the presence of two MN subpopulations and an ALS-specific dysregulation of glutamatergic and synaptic signaling. This ALS SC-chip model generates a diversity of mature MNs to better understand ALS pathology in a model that has an active blood-brain barrier-like system for future drug screening.
{"title":"An organ-chip model of sporadic ALS using iPSC-derived spinal cord motor neurons and an integrated blood-brain-like barrier","authors":"Deepti Lall, Michael J. Workman, Samuel Sances, Briana N. Ondatje, Shaughn Bell, George Lawless, Amanda Woodbury, Dylan West, Amanda Meyer, Andrea Matlock, Vineet Vaibhav, Jennifer E. Van Eyk, Clive N. Svendsen","doi":"10.1016/j.stem.2025.05.015","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.015","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder in which motor neurons (MNs) of the brain and spinal cord degenerate, leading to paralysis. Generating MNs from patient-specific induced pluripotent stem cells (iPSCs) may help elucidate early stages of disease. Here, we combined MNs from patients with early-onset disease with brain microvascular endothelial-like cells in a microfluidic device we termed spinal cord chips (SC-chips) and added media flow, which enhanced neuronal maturation and improved cellular health. Bulk transcriptomic and proteomic analyses of SC-chips revealed differences between control and ALS samples, including increased levels of neurofilaments. Single-nuclei RNA sequencing revealed the presence of two MN subpopulations and an ALS-specific dysregulation of glutamatergic and synaptic signaling. This ALS SC-chip model generates a diversity of mature MNs to better understand ALS pathology in a model that has an active blood-brain barrier-like system for future drug screening.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"27 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370930","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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