Cell stem cellPub Date : 2026-10-29DOI: 10.1016/j.stem.2026.10.004
Hamayl Afzal,Tomer Rotstein,Debolina D. Biswas,Xin Lin,Alastair Khodabukus,Wenzhe Luo,Yueyuan Xu,Emma C. Frair,Yongwu Li,Jingjuan Chen,Shihuan Kuang,Kevin M. Flanigan,Nenad Bursac,Mai K. ElMallah,Charles A. Gersbach,Yarui Diao
{"title":"Niche-reprogramming CAR T therapy improves skeletal muscle regeneration and function in preclinical murine models of Duchenne muscular dystrophy","authors":"Hamayl Afzal,Tomer Rotstein,Debolina D. Biswas,Xin Lin,Alastair Khodabukus,Wenzhe Luo,Yueyuan Xu,Emma C. Frair,Yongwu Li,Jingjuan Chen,Shihuan Kuang,Kevin M. Flanigan,Nenad Bursac,Mai K. ElMallah,Charles A. Gersbach,Yarui Diao","doi":"10.1016/j.stem.2026.10.004","DOIUrl":"https://doi.org/10.1016/j.stem.2026.10.004","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder with no cure. Emerging dystrophin-restoring gene therapies target mutant myofibers but face challenges in efficacy and toxicities, underscoring the need for new treatments. Current therapies do not address chronic inflammation and muscle fibrosis, key pathologies creating a pathological muscle microenvironment that impairs dystrophic muscle function and regeneration. Here, we identify urokinase plasminogen activator receptor (uPAR) as a shared surface marker on subsets of macrophages and fibro-adipogenic progenitors exhibiting strong pro-inflammatory and fibrogenic signatures in DMD. Notably, uPAR-directed chimeric antigen receptor (CAR) T cells selectively eliminate these pathogenic subpopulations, remodel the muscle microenvironment, and enhance dystrophic muscle regeneration and force production; they also improve diaphragm and respiratory function, addressing an unmet clinical need and a major cause of DMD mortality. These findings establish uPAR CAR T cells as a niche-remodeling regenerative immunotherapy that simultaneously addresses multiple DMD pathologies and improves dystrophic muscle regeneration and function.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"13 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149281650","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}
Cell stem cellPub Date : 2026-10-22DOI: 10.1016/j.stem.2026.09.015
Mohammad N. Taheri,Yuda Xiang,Chu Weng,Alex Hill,Tahere Mokhtari,Jennie Bostich,Joshua Hislop,Michael Oertel,Jason Lohmueller,Samira Kiani,Mo R. Ebrahimkhani
{"title":"Programmable apoptosis circuits enable subtractive engineering of stem cell-derived organoids and embryoids","authors":"Mohammad N. Taheri,Yuda Xiang,Chu Weng,Alex Hill,Tahere Mokhtari,Jennie Bostich,Joshua Hislop,Michael Oertel,Jason Lohmueller,Samira Kiani,Mo R. Ebrahimkhani","doi":"10.1016/j.stem.2026.09.015","DOIUrl":"https://doi.org/10.1016/j.stem.2026.09.015","url":null,"abstract":"Pluripotent stem cell-derived multicellular systems provide a promising platform for studying development and disease. However, they do not faithfully mirror their in vivo counterparts due to the presence of aberrant cells. Similarly, aberrant cell types emerge during tissue development in multicellular organisms but are effectively removed via proofreading mechanisms that often exploit apoptosis. Yet, the design and engineering of such processes are notably absent from current approaches for building stem cell-derived multicellular systems. We address this gap by introducing a “subtractive multicellular engineering” approach, using genetic circuits that integrate logic-gated computing and synthetic apoptosis. Through this approach, we enhance tissue maturity in human pluripotent stem cell-derived liver organoids. Additionally, we demonstrate the versatility of this approach in a human post-implantation embryo model, where it improves pro-amniotic cavity development, a key morphogenetic feature. Our results establish a framework for building tissues in vitro via controlled elimination of aberrant cells during morphogenesis.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"22 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149230052","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}
Cell stem cellPub Date : 2026-10-21DOI: 10.1016/j.stem.2026.09.014
Ana R. Pinho,Magda C. Henriques,Maria C. Gomes,João F. Mano
{"title":"A self-organized tri-lineage bone model in liquefied microcapsules captures matrix dynamics in early remodeling","authors":"Ana R. Pinho,Magda C. Henriques,Maria C. Gomes,João F. Mano","doi":"10.1016/j.stem.2026.09.014","DOIUrl":"https://doi.org/10.1016/j.stem.2026.09.014","url":null,"abstract":"Bone tissue is inherently complex, featuring specialized cells, a dynamic extracellular matrix (ECM), vascular networks, and continuous remodeling. These processes are tightly regulated by cell-cell and cell-ECM interactions, making them difficult to replicate in vitro. Here, we developed a self-regulated, bone-like three-dimensional microenvironment using liquefied microcapsules composed of hydroxypyridinone- and dopamine-modified gelatins, supporting scaffold structure and bioactivity. Bone marrow-derived human mesenchymal stromal cells (BM-hMSCs) and a human monocyte cell line (THP-1) were directly co-cultured in a 3:1 ratio for 35 days within the microcapsules. This heterotypic system, without exogenous differentiating inducers, supported differentiation into osteoblasts, osteocytes, and osteoclasts, alongside ECM deposition, mineralization, and resorption. Proteomic signatures further indicated features associated with bone development and early remodeling. This self-organized tri-lineage bone model provides a simplified tool for studying cellular crosstalk and ECM dynamics, with potential to reduce reliance on animal models.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"1 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225931","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}
{"title":"Phase separation of Rbpms sequesters translation elongation machinery to preserve hematopoietic stem cell function","authors":"Le Chang,Mengyao Sun,Lingyan Zhao,Jiahuan He,Sijia Bai,Zhongyang Chen,Siqi Liu,Xinyan Shen,Fanqi Zhou,Yu Rong,Chenxi Han,Yanmin Si,Hualu Zhao,Fang Wang,Yanni Ma,Jia Yu","doi":"10.1016/j.stem.2026.09.013","DOIUrl":"https://doi.org/10.1016/j.stem.2026.09.013","url":null,"abstract":"The mechanisms by which hematopoietic stem cells (HSCs) maintain long-term (LT) hematopoietic capacity and transition from quiescence remain incompletely understood, limiting their in vitro expansion and applications. Accumulating evidence underscores the importance of maintaining a low protein synthesis rate for HSC function, yet the underlying mechanisms remain elusive. Here, we identified ribosome-associated proteins specifically enriched in HSCs and multipotent progenitors (MPPs) and found that RNA-binding protein gene with multiple splicing (Rbpms) is required for sustaining low protein synthesis rates in HSCs. Rbpms forms biomolecular condensates that sequester translation elongation factors and protein-folding chaperones from ribosomes, slowing translation elongation and ensuring proper protein folding in HSCs. Rbpms deletion led to accelerated protein synthesis, accumulation of misfolded proteins in HSCs, impaired LT hematopoietic reconstitution capacity, accompanied by aberrant exit from quiescence. Our findings unveil a unique mechanism of translation elongation regulation in HSCs and highlight significance of spatial compartmentalization and translational control in HSCs.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"75 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225928","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}
{"title":"Skin fibroblast lineage tracing reveals layer-specific cooperation in wound repair","authors":"Zhihou Guo,Tianchang Xia,Zhuonan Zhang,Haichang Wang,Shun He,Xin Song,Ke Jia,Ximeng Han,Xiong Xiong,Yanxiao Zhang,Bin Zhou,Lingjuan He","doi":"10.1016/j.stem.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.stem.2026.09.010","url":null,"abstract":"Skin fibroblasts exhibit remarkable heterogeneity across their multilayered cutaneous architecture, yet their roles during wound repair remain elusive, mainly due to the lack of layer-specific genetic tools. Here, we employed a dual-recombinase strategy to develop genetic lineage-tracing tools for all five layers of skin fibroblasts: papillary, reticular, hypodermal, panniculus carnosus (PC), and fascia fibroblasts. Our study revealed an intricate spatiotemporal pattern of fibroblast contributions across different wound severities. Temporally, deep wounds elicited a sequential contribution of these fibroblasts in three stages, while superficial wounds involved two. The early-contributing fibroblasts predominantly occupied the wound bed during the closure stage, while subsequently recruited populations mainly entered during tissue remodeling and scar formation. Spatially, as remodeling progressed, fibroblasts reorganized into a hierarchical arrangement closely mirroring their pre-injury spatial distribution. Our study elucidates the coordinated spatiotemporal interplay of fibroblasts during wound repair and may spur novel therapeutic modalities and interventions for cutaneous healing.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"53 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173080","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}
Cell stem cellPub Date : 2026-10-15DOI: 10.1016/j.stem.2026.09.012
Leyla Anne Akay,Anna Bright,Daiyun Dong,Ethan D. Smith,Robert C. Hurt,Carles A. Boix,Kate Louderback,Janine Medrano,Dingcheng Sun,Haonan Lin,Oisín King,Gwyneth M. Welch,Hiba Nawaid,Emre Agbas,Alan Jiang,Adele Bubnys,Ji-Xin Cheng,Joel W. Blanchard,Li-Huei Tsai
{"title":"Genome-wide CRISPR screen reveals that Wnt signaling regulates lipid accumulation in APOE4 oligodendrocytes","authors":"Leyla Anne Akay,Anna Bright,Daiyun Dong,Ethan D. Smith,Robert C. Hurt,Carles A. Boix,Kate Louderback,Janine Medrano,Dingcheng Sun,Haonan Lin,Oisín King,Gwyneth M. Welch,Hiba Nawaid,Emre Agbas,Alan Jiang,Adele Bubnys,Ji-Xin Cheng,Joel W. Blanchard,Li-Huei Tsai","doi":"10.1016/j.stem.2026.09.012","DOIUrl":"https://doi.org/10.1016/j.stem.2026.09.012","url":null,"abstract":"APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease, yet the cellular mechanisms linking APOE variants to disease risk remain unclear. We previously found that APOE4 expression causes lipid droplet accumulation in oligodendrocytes, reducing myelination, but the underlying mechanisms were unknown. Using a genome-wide CRISPR screen and assay for transposase-accessible chromatin (ATAC) sequencing in human-induced pluripotent stem cell (iPSC)-derived oligodendrocytes, we identified decreased Wnt signaling and overactive glycogen synthase kinase-3 beta (GSK3B) as key regulators of lipid-droplet accumulation. Genetic and pharmacological inhibition of GSK3B reduced lipid droplets in APOE4 oligodendrocytes and increased myelination in three-dimensional iPSC-derived brain organoids. Pharmacological GSK3B inhibition also reduced lipid droplets and improved myelination in APOE4;PS19 tau transgenic mice. Together, these findings establish a mechanistic framework linking Wnt/GSK3B signaling to APOE4-driven disruptions in oligodendrocyte lipid metabolism and myelination, pointing to GSK3B as a potential therapeutic target for APOE4-associated Alzheimer’s disease.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"6 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173079","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}
Cell stem cellPub Date : 2026-10-13DOI: 10.1016/j.stem.2026.10.008
Robert P. Fordham,Shiro Yui,Nicholas R.F. Hannan,Christoffer Soendergaard,Alison Madgwick,Pawel J. Schweiger,Ole H. Nielsen,Ludovic Vallier,Roger A. Pedersen,Tetsuya Nakamura,Mamoru Watanabe,Kim B. Jensen
{"title":"Transplantation of Expanded Fetal Intestinal Progenitors Contributes to Colon Regeneration after Injury","authors":"Robert P. Fordham,Shiro Yui,Nicholas R.F. Hannan,Christoffer Soendergaard,Alison Madgwick,Pawel J. Schweiger,Ole H. Nielsen,Ludovic Vallier,Roger A. Pedersen,Tetsuya Nakamura,Mamoru Watanabe,Kim B. Jensen","doi":"10.1016/j.stem.2026.10.008","DOIUrl":"https://doi.org/10.1016/j.stem.2026.10.008","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"49 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152681","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}
{"title":"Rapid CAR-T manufacturing with low-intensity priming enhances CAR-T cell fitness and limits inflammatory programming in a phase 1 study","authors":"Zhi Yang,Shiqi Li,Linling Wang,Yunyan Li,Huailong Xu,Yu Li,Lin Liu,Zhongtao Yuan,Yingzi Zhang,Lihua Zhang,Yingnian Chen,Qianzhen Zhang,Junjie Shen,Meiling Wang,Wei Zhu,Xiao He,Youcheng Wang,Yancheng Dong,Sanbin Wang,Cheng Qian","doi":"10.1016/j.stem.2026.09.006","DOIUrl":"https://doi.org/10.1016/j.stem.2026.09.006","url":null,"abstract":"Conventional chimeric antigen receptor (CAR)-T manufacturing requires prolonged ex vivo activation and expansion, which may compromise T cell fitness and promote inflammatory differentiation. Here, we developed PrimeCAR, a 2-day manufacturing strategy combining low-intensity anti-CD3 priming with IL-7 and IL-21. Compared with conventionally manufactured CAR-T cells, PrimeCAR products exhibited a distinct transcriptional state characterized by preserved stemness-associated programs and a PrimeCAR-enriched primed naive T cell (Tn)-like state. Following antigen stimulation, PrimeCAR cells preferentially engaged proliferative programs while limiting exhaustion-associated regulators and inflammatory mediators. Functionally, PrimeCAR cells demonstrated enhanced expansion, persistence, and durable antitumor activity in xenograft models. In investigator-initiated phase I studies of relapsed or refractory B cell acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma, PrimeCAR showed encouraging clinical activity with a favorable safety profile. Together, these findings demonstrate that rapid manufacturing with controlled early T cell priming selectively restrains inflammatory programming while preserving CAR-T cell fitness, providing a practical strategy for improving CAR-T manufacturing and therapeutic performance.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"1 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152682","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}
{"title":"Single-cell CRISPR screen maps epigenetic regulators of lineage specification and malignancies in human HSPCs","authors":"Shiru Yuan,Shangda Yang,Yaojin Huang,Baowei Ma,Qian Wu,Xinghui Zhang,Tong Yin,Lianting Chen,Baixuan Zhang,Guohuan Sun,Yicheng He,Honglin Duan,Linping Hu,Sha Hao,Hui Cheng,Jun Wei,Tao Cheng","doi":"10.1016/j.stem.2026.09.005","DOIUrl":"https://doi.org/10.1016/j.stem.2026.09.005","url":null,"abstract":"Mapping how genetic perturbations influence cell fate is key to understanding human development and disease. Here, we developed a massively parallel single-cell CRISPR (scCRISPR) screening platform in primary human hematopoietic stem and progenitor cells (HSPCs), profiling 322 regulators across 172,382 single-perturbed cells. The resulting multi-layered regulatory framework captured known associations and enabled functional annotation of regulator-phenotype relationships. Specifically, our atlas revealed that regulators acted within perturbation clusters to govern distinct gene programs that shaped cell fate. As proof of concept, we illustrated several examples. SMYD3 emerged as a negative regulator of long-term regenerative capacity. Analysis of lineage output further identified KMT5B, TRIM24, SETD7, and NSD3 as regulators associated with lineage-biased outputs. Finally, integration with clinical datasets identified PRDM10 as a candidate dependency in acute myeloid leukemia (AML). This work establishes a scalable functional genomics platform in a primary human stem cell system.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"21 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152686","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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