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In vivo CAR-Tfh cell reprogramming restores tolerance in a mouse model of autoimmune hepatitis 体内CAR-Tfh细胞重编程恢复自身免疫性肝炎小鼠模型的耐受性
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-03-13 DOI: 10.1016/j.stem.2026.02.006
Zuolin Zheng, Ying Liu, Ganyu Wang, Xinyuan Li, Shengxuan Peng, Zhen Jia, Xiao Yue, Zhipeng Fu, Xiaotian Zhao, Maosen Han, Zhenmei Yang, Chunwei Tang, Jinxin Gao, Zhichao Kong, Chen Chen, Kun Zhao, Tao Li, Xinyi Jiang, Weiqiang Jing
{"title":"In vivo CAR-Tfh cell reprogramming restores tolerance in a mouse model of autoimmune hepatitis","authors":"Zuolin Zheng, Ying Liu, Ganyu Wang, Xinyuan Li, Shengxuan Peng, Zhen Jia, Xiao Yue, Zhipeng Fu, Xiaotian Zhao, Maosen Han, Zhenmei Yang, Chunwei Tang, Jinxin Gao, Zhichao Kong, Chen Chen, Kun Zhao, Tao Li, Xinyi Jiang, Weiqiang Jing","doi":"10.1016/j.stem.2026.02.006","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.006","url":null,"abstract":"Autoimmune diseases involve the coordinated dysregulation of multiple types of immune cells, and single-cell targeted therapies often yield suboptimal results. Here, we developed chimeric antigen receptor (CAR)-engineered follicular helper T (Tfh) cells capable of simultaneously suppressing T cells, B cells, and dendritic cells (DCs) to restore immune homeostasis in an autoimmune hepatitis (AIH) mouse model. Using amino acid-derived lipid nanoparticles, we deliver self-amplifying RNA encoding Forkhead box protein P3 (Foxp3) and a cytochrome P4502D6 (CYP2D6)-specific CAR to Tfh cells, conferring stable regulatory features and antigen-dependent suppressive activity. Engineered CAR-Tfh cells preferentially localize to the liver, recognize CYP2D6-expressing hepatocytes, and suppress pathogenic T cell and B cell responses. In AIH-II mouse models, CAR-Tfh cell generation restores a tolerogenic hepatic immune environment and ameliorates autoimmune liver injury. These findings establish <em>in situ</em> Tfh cell reprogramming as a modular approach to coordinately modulate multiple immune compartments, providing a potential therapeutic framework for AIH and related autoimmune diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439684","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}
引用次数: 0
Modeling human prenatal adrenocortical functional zonation dynamics from pluripotent stem cells. 用多能干细胞模拟人产前肾上腺皮质功能分区动力学。
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-03-05 DOI: 10.1016/j.stem.2026.02.002
Michinori Mayama,Eoin C Whelan,Takeshi Sato,David G Stouffer,Adrian N Leu,Jerome F Strauss,Richard J Auchus,Kotaro Sasaki
{"title":"Modeling human prenatal adrenocortical functional zonation dynamics from pluripotent stem cells.","authors":"Michinori Mayama,Eoin C Whelan,Takeshi Sato,David G Stouffer,Adrian N Leu,Jerome F Strauss,Richard J Auchus,Kotaro Sasaki","doi":"10.1016/j.stem.2026.02.002","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.002","url":null,"abstract":"The adrenal cortex produces essential steroid hormones through a concentric zonal architecture, established by the centripetal transdifferentiation of subcapsular progenitors within a capsule-derived niche. To capture this complexity, we establish a human pluripotent stem cell-derived adrenal organoid system that faithfully recapitulates this process. RSPO3/WNT signaling from the capsule specifies definitive zone (DZ) progenitors from the adrenal primordium, which then differentiate into a cortisol-producing transitional zone and an androgen-producing fetal zone under the influence of RSPO3 and ACTH. Loss of NR0B1 impairs DZ specification and triggers direct adrenal primordium-to-fetal zone conversion, mirroring the mechanism of X-linked adrenal hypoplasia congenita. When DZ cells are encapsulated with capsule cells separately derived from pluripotent stem cells, they reconstitute zonation in vivo, forming ACTH-responsive tissue that produces both cortisol and androgens. This organoid platform offers a powerful tool to dissect human adrenal development and establishes a foundation for regenerative therapies targeting adrenal diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"56 1","pages":"454-469.e9"},"PeriodicalIF":23.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147371019","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}
引用次数: 0
Adult neurogenesis: New neurons, new opportunities. 成人神经发生：新的神经元，新的机会。
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-03-05 DOI: 10.1016/j.stem.2026.01.014
Birte Doludda,Warsha Barde,Francesco D'Egidio,Carlos P Fitzsimons,Jonas Frisén,Fred H Gage,Sebastian Jessberger,Orly Lazarov,D Chichung Lie,Paul J Lucassen,Chiara de Lucia,Evgenia Salta,Hongjun Song,Juan Song,Sandrine Thuret,Tomohisa Toda,Gerd Kempermann
{"title":"Adult neurogenesis: New neurons, new opportunities.","authors":"Birte Doludda,Warsha Barde,Francesco D'Egidio,Carlos P Fitzsimons,Jonas Frisén,Fred H Gage,Sebastian Jessberger,Orly Lazarov,D Chichung Lie,Paul J Lucassen,Chiara de Lucia,Evgenia Salta,Hongjun Song,Juan Song,Sandrine Thuret,Tomohisa Toda,Gerd Kempermann","doi":"10.1016/j.stem.2026.01.014","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.014","url":null,"abstract":"The 38 currently registered clinical trials with the keyword \"adult neurogenesis\" indicate growing interest in new neurons as a target for intervention. Today, we have strong evidence that adult neurogenesis is involved in hippocampal function and can contribute to brain functions in health and disease. Neurogenesis research can now ask new questions, such as (1) the identity of stem cells and their input integration for initiating neurogenesis, (2) the nature of the neurogenic niche and neurogenesis without stem cell activity, (3) the complex functionality beyond the hippocampus, and (4) evolutionary and computational theory, including neurogenic neural networks for artificial intelligence.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"56 1","pages":"382-392"},"PeriodicalIF":23.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370993","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}
引用次数: 0
Off-the-shelf CAR natural killer progenitor cell therapies are built to last. 现成的CAR自然杀伤祖细胞疗法是持久的。
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-03-05 DOI: 10.1016/j.stem.2026.02.004
Noor Radde,Max Jan
{"title":"Off-the-shelf CAR natural killer progenitor cell therapies are built to last.","authors":"Noor Radde,Max Jan","doi":"10.1016/j.stem.2026.02.004","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.004","url":null,"abstract":"Induced pluripotent stem cell (iPSC)-derived chimeric antigen receptor (CAR) natural killer (NK) cells are an emerging class of off-the-shelf cellular immunotherapy limited by short-term persistence. Wang et al.1 develop a platform for lineage-committed progenitor cell therapy to sustain in vivo CAR iNK cell lymphopoiesis and enhance tumor control.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"32 1","pages":"366-368"},"PeriodicalIF":23.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370999","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}
引用次数: 0
Neuronal VIP shapes intestinal stem cell activity and mucosal immunity. 神经元VIP影响肠干细胞活性和粘膜免疫。
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-03-05 DOI: 10.1016/j.stem.2026.02.001
Camilla Anastasio,Lucie Peduto
{"title":"Neuronal VIP shapes intestinal stem cell activity and mucosal immunity.","authors":"Camilla Anastasio,Lucie Peduto","doi":"10.1016/j.stem.2026.02.001","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.001","url":null,"abstract":"Intestinal homeostasis and regeneration rely on intestinal stem cells (ISCs). Li et al.1 identified neuronal vasoactive intestinal peptide (VIP) as a brake on ISCs through VIPR1 to limit regeneration. In Nature Immunology, Jakob et al. and Pirzgalska et al. further showed that VIP-VIPR1 signaling restrains secretory lineage expansion and balances immune responses.2,3.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"9 1","pages":"361-362"},"PeriodicalIF":23.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147371003","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}
引用次数: 0
Tissues assemble! Rebuilding the human periportal liver in a dish. 组织组装!在培养皿中重建人类门静脉周围肝脏。
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-03-05 DOI: 10.1016/j.stem.2026.02.005
Scott H Waddell,Luke Boulter
{"title":"Tissues assemble! Rebuilding the human periportal liver in a dish.","authors":"Scott H Waddell,Luke Boulter","doi":"10.1016/j.stem.2026.02.005","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.005","url":null,"abstract":"In their recent Nature paper, Yuan et al. reconstruct patient-specific periportal architecture by assembling hepatocyte organoids with cholangiocytes and portal mesenchyme. Unlike previous attempts, these multicellular units recapitulate much of the cell-cell interaction found in the adult human liver, providing a new sophisticated platform to understand liver biology.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"4 1","pages":"369-371"},"PeriodicalIF":23.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370995","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}
引用次数: 0
Two decades of induced pluripotent stem cell research: From discovery to diverse applications. 诱导多能干细胞研究二十年：从发现到多种应用。
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-03-05 DOI: 10.1016/j.stem.2026.02.003
Shinya Yamanaka
{"title":"Two decades of induced pluripotent stem cell research: From discovery to diverse applications.","authors":"Shinya Yamanaka","doi":"10.1016/j.stem.2026.02.003","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.003","url":null,"abstract":"Twenty years have passed since the first demonstration of mouse induced pluripotent stem cells (iPSCs). What began as an unexpected observation in Kyoto quickly transformed stem cell biology and regenerative medicine worldwide. Over the past two decades, we have gained profound insights into the molecular mechanisms underlying cellular reprogramming and pluripotency. The technology has continued to evolve-becoming safer, more efficient, and more versatile. Today, iPSCs serve as a foundation for wide-ranging applications, from disease modeling and drug discovery to regenerative therapies and rejuvenation research. In this review, I reflect on the scientific journey of iPSCs, highlight key milestones in our understanding of reprogramming, and discuss the expanding clinical and societal impact of iPSCs.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"45 1","pages":"372-381"},"PeriodicalIF":23.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370996","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}
引用次数: 0
Cradles for maturation: Turning progenitor cells into functional intestinal epithelium. 成熟的摇篮：将祖细胞转化为功能性肠上皮。
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-03-05 DOI: 10.1016/j.stem.2026.01.016
Kaustav Bera,Kristi S Anseth
{"title":"Cradles for maturation: Turning progenitor cells into functional intestinal epithelium.","authors":"Kaustav Bera,Kristi S Anseth","doi":"10.1016/j.stem.2026.01.016","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.016","url":null,"abstract":"Maimets et al.1 reveal that appropriate tissue shape is required during maturation of the intestinal epithelium from the fetal to adult state, and this transition is mediated by the mechanotransduction protein-YAP. The introduced method transforms fetal cells into mature, functional cells in vitro, unachievable by traditional three-dimensional cultures.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"298 1","pages":"363-365"},"PeriodicalIF":23.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370997","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}
引用次数: 0
Randomized phase 2b dose-escalation trial of stem cell therapy with laromestrocel for aging frailty laromestocel干细胞治疗衰老虚弱的随机2b期剂量递增试验
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-02-25 DOI: 10.1016/j.stem.2026.01.017
Jorge G. Ruiz, Anthony A. Oliva, Kevin N. Ramdas, Julian Javier, Jeffrey Rosen, Robert Perry, Antonio Blanco, Pedro Ylisastigui, Jeremy Walston, Hidenori Arai, Elena Volpi, Anne B. Newman, Brittany Varnado, Lisa McClain-Moss, Eric Naioti, Danial Mehranfard, Dan Gincel, Chao Wang, Michael J. Mintzer, Joel Danisi, Joshua M. Hare
{"title":"Randomized phase 2b dose-escalation trial of stem cell therapy with laromestrocel for aging frailty","authors":"Jorge G. Ruiz, Anthony A. Oliva, Kevin N. Ramdas, Julian Javier, Jeffrey Rosen, Robert Perry, Antonio Blanco, Pedro Ylisastigui, Jeremy Walston, Hidenori Arai, Elena Volpi, Anne B. Newman, Brittany Varnado, Lisa McClain-Moss, Eric Naioti, Danial Mehranfard, Dan Gincel, Chao Wang, Michael J. Mintzer, Joel Danisi, Joshua M. Hare","doi":"10.1016/j.stem.2026.01.017","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.017","url":null,"abstract":"Frailty, a syndrome that decreases healthspan in older individuals, lacks effective therapies. We conducted a randomized, dose-finding clinical trial to test whether human bone marrow-derived allogeneic mesenchymal stem cells (MSCs; laromestrocel) improve physical functioning and patient self-reported outcomes in ambulatory individuals with frailty (<span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span> #NCT03169231; <em>N =</em> 148). Laromestrocel infusion results in clinically meaningful, dose- and time-dependent increases in the 6-min walk test (6MWT; primary endpoint) compared with placebo: 63.4 m (95% confidence interval [CI]: 17.1–109.6 m; <em>p =</em> 0.0077) at month 9 and 41.3 m (95% CI: −2.4–84.9 m; <em>p =</em> 0.0635) at month 6. Increased 6MWT distance correlates with PROMIS Physical Function score, and increasing doses of laromestrocel are associated with decreases in soluble (degraded) tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE2), the cognate receptor for the angiopoietins, identifying a potential biomarker of laromestrocel responsiveness. These findings identify a stem cell therapy approach for the management of patients with hypomobility and other features of aging frailty.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"18 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147279391","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}
引用次数: 0
Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity 在基因组编辑中最大限度地减少远延伸的染色质扰动，保持干细胞的身份
IF 23.9 1区 医学
Cell stem cell Pub Date : 2026-02-24 DOI: 10.1016/j.stem.2026.01.015
Ming Zhu, Junsong Yuan, Qiuchen Meng, Jiawei Yu, Xiaoqing Xu, Mingyue Xu, Xiaoyu Ren, Yanyan Hu, Guoan Wei, Zeran Jia, Guohua Yuan, Lu Zang, Shaorui Liu, Yuanyuan Yang, Yuan Zheng, Jiacheng Wang, Tingting Cong, Wei Xie, Xun Lan, Le Cong, Tianhua Ma, Sheng Ding, Weixiang Guo, Xuegong Zhang, Yinqing Li
{"title":"Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity","authors":"Ming Zhu, Junsong Yuan, Qiuchen Meng, Jiawei Yu, Xiaoqing Xu, Mingyue Xu, Xiaoyu Ren, Yanyan Hu, Guoan Wei, Zeran Jia, Guohua Yuan, Lu Zang, Shaorui Liu, Yuanyuan Yang, Yuan Zheng, Jiacheng Wang, Tingting Cong, Wei Xie, Xun Lan, Le Cong, Tianhua Ma, Sheng Ding, Weixiang Guo, Xuegong Zhang, Yinqing Li","doi":"10.1016/j.stem.2026.01.015","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.015","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"18 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147278977","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}
引用次数: 0
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