Transplantation of pluripotent stem cell-derived islets (PSC-islets), containing functional insulin-producing β cells, represents promising cell therapy for restoring glycemic control in diabetes. However, recapitulation of complete endocrine composition in PSC-islets remains challenging, and their ability to counteract hazardous hypoglycemia, crucial to metabolic safety in vivo, remains unexplored. Here, we report robust generation of non-β cells in vitro. By incorporating non-β and β cells, we report reconstruction of PSC-islets comprising all five (α, β, δ, ε, and γ) endocrine subtypes (reconstructed PSC-islets). After reversal of hyperglycemia in diabetic mouse models, these islets exhibited robust protection against hypoglycemia, with only 3% of measurements falling below 54 mg/dL compared with 59% in non-reconstructed controls. Remarkably, hypoglycemic clamp assays suggested restoration of previously defective counterregulatory response in reconstructed PSC-islet recipients. These findings establish a strategy to control relative abundance of PSC-islet subtypes, providing a basis for calibrating post-transplant glycemic homeostasis with definitive hypoglycemic protection.
{"title":"Reconstruction of endocrine subtype-complete human pluripotent stem cell-derived islets with capacity for hypoglycemia protection in vivo","authors":"Gaofan Meng, Jiabin Gu, Soon Yi Liew, Jingxiao Cao, Zhihui Wang, Chunyu Ma, Zhenzhen Fu, Hongwen Zhou, Jinlin Wang, Shusen Wang, Sijia Jing, Yiqi Wu, Zhengjun Lei, Shuli Zhi, Yuanyuan He, Cheng Li, Hongkui Deng","doi":"10.1016/j.stem.2025.07.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.006","url":null,"abstract":"Transplantation of pluripotent stem cell-derived islets (PSC-islets), containing functional insulin-producing β cells, represents promising cell therapy for restoring glycemic control in diabetes. However, recapitulation of complete endocrine composition in PSC-islets remains challenging, and their ability to counteract hazardous hypoglycemia, crucial to metabolic safety <em>in vivo</em>, remains unexplored. Here, we report robust generation of non-β cells <em>in vitro</em>. By incorporating non-β and β cells, we report reconstruction of PSC-islets comprising all five (α, β, δ, ε, and γ) endocrine subtypes (reconstructed PSC-islets). After reversal of hyperglycemia in diabetic mouse models, these islets exhibited robust protection against hypoglycemia, with only 3% of measurements falling below 54 mg/dL compared with 59% in non-reconstructed controls. Remarkably, hypoglycemic clamp assays suggested restoration of previously defective counterregulatory response in reconstructed PSC-islet recipients. These findings establish a strategy to control relative abundance of PSC-islet subtypes, providing a basis for calibrating post-transplant glycemic homeostasis with definitive hypoglycemic protection.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"20 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797236","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 : 2025-08-07DOI: 10.1016/j.stem.2025.07.005
Alperen Yilmaz, Gulben Gurhan, Mehmet-Yunus Comar, Sergey Viukov, Inbal Serfaty, Mert Gayretli, Sergey Golenchenko, Dmitry Lokshtanov, Shahd Ashouokhi, Angel Polanco, Idan Berlad, Tae-Won Ha, Alejandro Aguilera-Castrejon, Shadi Tarazi, Marina Cohen, Nir Livnat, Komal Kumar, Hisham Cholakkal, Nathan Levy, Nir Yosef, Jacob H. Hanna
The generation of post-gastrulation stem cell-derived mouse embryo models (SEMs) exclusively from naive embryonic stem cells (nESCs) has underscored their ability to give rise to embryonic and extra-embryonic lineages. However, existing protocols for mouse SEMs rely on the separate induction of extra-embryonic lineages and on ectopic expression of transcription factors to induce nESC differentiation into trophectoderm (TE) or primitive endoderm (PrE). Here, we demonstrate that mouse nESCs and naive induced pluripotent stem cells (niPSCs) can be simultaneously co-induced, via signaling pathway modulation, to generate PrE and TE extra-embryonic cells that self-organize into embryonic day (E) 8.5–E8.75 transgene-free (TF) SEMs. We also devised an alternative condition (AC) naive media that in vitro stabilizes TF-SEM-competent OCT4+/NANOG+ nESC colonies that co-express antagonistic CDX2 and/or GATA6 extra-embryonic fate master regulators and self-renew while remaining poised for TE and PrE differentiation, respectively. These findings improve mouse SEM strategies and shed light on amplifying an inherent and dormant extra-embryonic plasticity of mouse naive pluripotent cells in vitro.
{"title":"Transgene-free generation of mouse post-gastrulation whole embryo models solely from naive ESCs and iPSCs","authors":"Alperen Yilmaz, Gulben Gurhan, Mehmet-Yunus Comar, Sergey Viukov, Inbal Serfaty, Mert Gayretli, Sergey Golenchenko, Dmitry Lokshtanov, Shahd Ashouokhi, Angel Polanco, Idan Berlad, Tae-Won Ha, Alejandro Aguilera-Castrejon, Shadi Tarazi, Marina Cohen, Nir Livnat, Komal Kumar, Hisham Cholakkal, Nathan Levy, Nir Yosef, Jacob H. Hanna","doi":"10.1016/j.stem.2025.07.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.005","url":null,"abstract":"The generation of post-gastrulation stem cell-derived mouse embryo models (SEMs) exclusively from naive embryonic stem cells (nESCs) has underscored their ability to give rise to embryonic and extra-embryonic lineages. However, existing protocols for mouse SEMs rely on the separate induction of extra-embryonic lineages and on ectopic expression of transcription factors to induce nESC differentiation into trophectoderm (TE) or primitive endoderm (PrE). Here, we demonstrate that mouse nESCs and naive induced pluripotent stem cells (niPSCs) can be simultaneously co-induced, via signaling pathway modulation, to generate PrE and TE extra-embryonic cells that self-organize into embryonic day (E) 8.5–E8.75 transgene-free (TF) SEMs. We also devised an alternative condition (AC) naive media that <em>in vitro</em> stabilizes TF-SEM-competent OCT4+/NANOG+ nESC colonies that co-express antagonistic CDX2 and/or GATA6 extra-embryonic fate master regulators and self-renew while remaining poised for TE and PrE differentiation, respectively. These findings improve mouse SEM strategies and shed light on amplifying an inherent and dormant extra-embryonic plasticity of mouse naive pluripotent cells <em>in vitro</em>.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"9 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792325","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 : 2025-08-07DOI: 10.1016/j.stem.2025.07.001
Maria A. Telpoukhovskaia, Jennifer J. Trowbridge
While clonal hematopoiesis (CH) is associated with protection from Alzheimer’s disease (AD), a limited understanding of the mechanisms by which this occurs has been a barrier to therapeutic intervention. In a new study, Matatall et al.1 discover protective mechanisms by which TET2-mutant, but not DNMT3A-mutant, CH impacts dementia pathology and cognition.
{"title":"Plot twist: TET2 clones save the brain","authors":"Maria A. Telpoukhovskaia, Jennifer J. Trowbridge","doi":"10.1016/j.stem.2025.07.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.001","url":null,"abstract":"While clonal hematopoiesis (CH) is associated with protection from Alzheimer’s disease (AD), a limited understanding of the mechanisms by which this occurs has been a barrier to therapeutic intervention. In a new study, Matatall et al.<span><span><sup>1</sup></span></span> discover protective mechanisms by which <em>TET2</em>-mutant, but not <em>DNMT3A</em>-mutant, CH impacts dementia pathology and cognition.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"1 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792326","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 : 2025-08-07DOI: 10.1016/j.stem.2025.07.002
Danielle Klinger, Jeffrey A. Naftaly, Kristy Red-Horse
Gong et al. present a transcription factor-guided 3D differentiation that rapidly generates vascular organoids from human iPSCs, enhancing engraftment and revascularization of ischemic limbs and transplanted pancreatic islets in mouse models.1 This approach establishes a scalable platform for generating functional vasculature, supporting both disease modeling and regenerative therapy development.
{"title":"Vascular organoids get a speed boost for regenerative repair","authors":"Danielle Klinger, Jeffrey A. Naftaly, Kristy Red-Horse","doi":"10.1016/j.stem.2025.07.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.002","url":null,"abstract":"Gong et al. present a transcription factor-guided 3D differentiation that rapidly generates vascular organoids from human iPSCs, enhancing engraftment and revascularization of ischemic limbs and transplanted pancreatic islets in mouse models.<span><span><sup>1</sup></span></span> This approach establishes a scalable platform for generating functional vasculature, supporting both disease modeling and regenerative therapy development.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"6 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792324","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 : 2025-08-07DOI: 10.1016/j.stem.2025.06.011
Kewen Hu, Yajie Chen, Zhen Zhang
The poor survival of islets post-transplantation remains a significant challenge for type 1 diabetes mellitus (T1DM) therapy. Vandana et al.1 develop ChemPerturb-seq, which is integrated with in vivo barcoded screening to identify small molecule cocktails that enhance human beta cell and islet survival after transplantation, offering promising strategies for T1DM.
{"title":"Revolutionizing islet transplantation with a preconditioning boost for beta cell survival","authors":"Kewen Hu, Yajie Chen, Zhen Zhang","doi":"10.1016/j.stem.2025.06.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.011","url":null,"abstract":"The poor survival of islets post-transplantation remains a significant challenge for type 1 diabetes mellitus (T1DM) therapy. Vandana et al.<span><span><sup>1</sup></span></span> develop ChemPerturb-seq, which is integrated with <em>in vivo</em> barcoded screening to identify small molecule cocktails that enhance human beta cell and islet survival after transplantation, offering promising strategies for T1DM.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"52 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792336","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 : 2025-08-01DOI: 10.1016/j.stem.2025.07.011
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
No Abstract
没有抽象的
{"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.2025.07.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.011","url":null,"abstract":"No Abstract","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"20 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756629","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 : 2025-07-30DOI: 10.1016/j.stem.2025.07.004
Guillermo C. Rivera-Gonzalez, Emily G. Butka, Carolynn E. Gonzalez, Rachel L. Mintz, Sarah S. Kleb, Violet Josephson, Wenjun Kong, Kunal Jindal, Kenji Kamimoto, Brett A. Shook, Matthew S. Rodeheffer, Samantha A. Morris
White adipose tissue supports essential physiological functions through adipocyte precursor cells (APCs), comprising progenitors and preadipocytes, which generate mature adipocytes during depot expansion. Using single-cell RNA sequencing-based lineage tracing, we characterize APCs in skin adipose tissue—a depot uniquely capable of rapid adipogenesis compared with other sites, such as inguinal adipose. We identify a previously uncharacterized population of immature preadipocytes and reveal distinct differentiation potentials among APCs. Contrary to traditional stepwise differentiation models, progenitors predominantly generate committed preadipocytes, whereas preexisting preadipocytes accumulate in immature states with divergent potential. Leveraging this refined APC hierarchy, we uncover Sox9 as a crucial regulator of progenitor proliferation and adipogenic differentiation. Cross-depot transplantation further demonstrates how intrinsic and extrinsic factors differentially regulate skin progenitor behavior, highlighting distinct adipogenic dynamics between skin and inguinal depots. Together, these insights redefine the cellular hierarchy and molecular mechanisms underpinning rapid adipogenesis in skin adipose tissue.
{"title":"Comparative single-cell lineage tracing identifies distinct adipocyte precursor dynamics in skin and inguinal fat","authors":"Guillermo C. Rivera-Gonzalez, Emily G. Butka, Carolynn E. Gonzalez, Rachel L. Mintz, Sarah S. Kleb, Violet Josephson, Wenjun Kong, Kunal Jindal, Kenji Kamimoto, Brett A. Shook, Matthew S. Rodeheffer, Samantha A. Morris","doi":"10.1016/j.stem.2025.07.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.004","url":null,"abstract":"White adipose tissue supports essential physiological functions through adipocyte precursor cells (APCs), comprising progenitors and preadipocytes, which generate mature adipocytes during depot expansion. Using single-cell RNA sequencing-based lineage tracing, we characterize APCs in skin adipose tissue—a depot uniquely capable of rapid adipogenesis compared with other sites, such as inguinal adipose. We identify a previously uncharacterized population of immature preadipocytes and reveal distinct differentiation potentials among APCs. Contrary to traditional stepwise differentiation models, progenitors predominantly generate committed preadipocytes, whereas preexisting preadipocytes accumulate in immature states with divergent potential. Leveraging this refined APC hierarchy, we uncover Sox9 as a crucial regulator of progenitor proliferation and adipogenic differentiation. Cross-depot transplantation further demonstrates how intrinsic and extrinsic factors differentially regulate skin progenitor behavior, highlighting distinct adipogenic dynamics between skin and inguinal depots. Together, these insights redefine the cellular hierarchy and molecular mechanisms underpinning rapid adipogenesis in skin adipose tissue.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"27 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737519","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}
Chemical reprogramming offers a fundamentally innovative approach for generating human chemically induced pluripotent stem (hCiPS) cells using small molecules. Our recent studies showed that this approach was highly efficient in reprogramming human fibroblasts to hCiPS cells. However, generating hCiPS cells from human blood cells, which are the most accessible and convenient source for reprogramming, remains a challenge. In this study, we established a robust method that successfully generated hCiPS cells from both cord blood and adult peripheral blood cells. This method achieved efficient reprogramming with both fresh and cryopreserved blood cells across different donors. Notably, this method also efficiently generated an average of over 100 hCiPS colonies from just a single drop of fingerstick blood. These results highlight the advantages of chemical reprogramming for generating hCiPS cells from a blood source and represent a next-generation platform for efficient, scalable, and convenient stem cell production with broad applications in regenerative medicine.
{"title":"Chemical reprogramming of human blood cells to pluripotent stem cells","authors":"Fangqi Peng, Yanglu Wang, Lin Cheng, Ruyi Cai, Xiaodi Fu, Zhihan Yang, Ruoqi Cheng, Weizhen Zeng, Yingshuai Dong, Jingxiao Cao, Jingping Mao, Jingran Zeng, Tianxing Liu, Guanxian Chen, Qi Lei, Lipeng Wang, Lulu Liu, Shicheng Sun, Cheng Li, Rong Mu, Hongkui Deng","doi":"10.1016/j.stem.2025.07.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.003","url":null,"abstract":"Chemical reprogramming offers a fundamentally innovative approach for generating human chemically induced pluripotent stem (hCiPS) cells using small molecules. Our recent studies showed that this approach was highly efficient in reprogramming human fibroblasts to hCiPS cells. However, generating hCiPS cells from human blood cells, which are the most accessible and convenient source for reprogramming, remains a challenge. In this study, we established a robust method that successfully generated hCiPS cells from both cord blood and adult peripheral blood cells. This method achieved efficient reprogramming with both fresh and cryopreserved blood cells across different donors. Notably, this method also efficiently generated an average of over 100 hCiPS colonies from just a single drop of fingerstick blood. These results highlight the advantages of chemical reprogramming for generating hCiPS cells from a blood source and represent a next-generation platform for efficient, scalable, and convenient stem cell production with broad applications in regenerative medicine.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"300 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737520","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 : 2025-07-17DOI: 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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：