{"title":"Perturb-seq uncovers pathological obstacles to direct cardiac reprogramming in vivo.","authors":"Yihong Cai,Yang Yang,Junbo Yang,Ruohan Ding,Qihan Zhang,Xin Dang,Chenxuan Li,Yang Zhao","doi":"10.1016/j.stem.2026.03.006","DOIUrl":"https://doi.org/10.1016/j.stem.2026.03.006","url":null,"abstract":"Direct induction of cardiomyocytes from fibroblasts represents a promising strategy for cardiac regeneration. However, the transdifferentiation efficiency in vivo remains low. Leveraging a Perturb-seq platform tailored to complex pathological environments, we systematically compared and ranked 140 potential barriers of in vivo cardiac reprogramming. Based on their shRNA distribution and enrichment along the single-cell RNA-seq trajectory, calreticulin (Calr) emerged as a top inhibitor. Calr knockdown greatly enhanced iCM induction efficiency in vitro, enabling synchronized calcium oscillations in iCMs, and accelerated in situ reprogramming after myocardial infarction, improving cardiac function and reducing fibrosis. Mechanistically, Calr knockdown activates calcium signaling, boosting MEF2C activity to drive reprogramming and even substitute for exogenous MEF2C. Collectively, our study reveals critical regulators hindering in situ cardiomyocyte induction in a pathological microenvironment, providing effective reprogramming factors and a strategic framework for cardiac repair and regeneration after myocardial infarction.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"87 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147584117","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":"Engineered MSCs enable bone marrow-targeted immunomodulation.","authors":"Shuyue Xu,Jingwen Xu,Qiqi Yang,Ju Zeng,Mengjie Zhang,Yuge Wu,Zhen Liu,Qun Wang,Qing You,Shiyi Zhang","doi":"10.1016/j.stem.2026.03.003","DOIUrl":"https://doi.org/10.1016/j.stem.2026.03.003","url":null,"abstract":"Tumors are increasingly recognized as a consequence of systemic immune dysregulation, while current therapies merely focus on direct tumor killing or local immune activation, overlooking the systemic immune landscape that enables tumorigenesis and metastasis. Targeting distal immune organs, such as the bone marrow (BM), without perturbing tumors remains challenging. Here, we develop a BM-targeted and tumor-evasive cell vector that restricts immunomodulation to the BM niche, enabling systemic immune reprogramming through niche-derived signaling. This mesenchymal stem cell (MSC)-based vector overexpresses Golgi apparatus protein 1 (MSCGlg1) to mimic BM affinity signals. In a myelosuppression model, MSCGlg1 delivers CDK4/6 inhibitors (CDK4/6i) to protect hematopoietic stem and progenitor cells (HSPCs) from chemotherapy toxicity while preserving antitumor efficacy. In a subcutaneous tumor model, MSCGlg1 delivers interleukin-7 (IL-7), restoring immune competence without promoting tumor proliferation. This strategy establishes a versatile framework for targeted immunomodulation to treat cancer as a systemic immune disease.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"220 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524393","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":"SPTEdU-seq enables parallel optics-free newborn cell tracking and spatial total transcriptional dynamics in intact microenvironments.","authors":"Haofu Niu,Shuang Zhang,Jizhong Mao,Yimian Wu,Yuting Chen,Jianhui Chen,Renying Wang,Guodong Zhang,Peijing Zhang,Xinlian Zhang,Siqi Wang,Danmei Jia,Jingjing Wang,Libin Zhou,Maode Lai,Guoji Guo,Xiaoping Han","doi":"10.1016/j.stem.2026.03.001","DOIUrl":"https://doi.org/10.1016/j.stem.2026.03.001","url":null,"abstract":"Understanding biological processes requires spatiotemporal mapping of proliferative and transcriptional dynamics. Current spatial transcriptomics methods capture only protein-coding transcripts and static snapshots, obscuring non-coding RNAs (ncRNAs) and dynamic events. We developed SPTEdU-seq, integrating spatial total transcriptomics with 5-ethynyl-2'-deoxyuridine tracking to co-profile gene expression and proliferation dynamics. SPTEdU-seq demonstrates ultrahigh sensitivity for coding and non-coding transcripts and for splicing isoforms, with single-molecule probe design eliminating optical imaging. Applied to developing and adult mouse brains, it revealed spatial lncRNA patterns, reconstructed developmental trajectories, and enabled spatiotemporal lineage tracing. In murine ischemic stroke, it mapped regeneration dynamics and identified an Igfbp5+ astrocyte subtype within a pro-repair niche. In mouse and human renal tumors, it uncovered tumor-associated splicing and detected diagnostic 3p loss. By profiling newborn and resident cells in intact microenvironments, it unveiled previously inaccessible interaction networks. SPTEdU-seq thus establishes a powerful framework for investigating cell fate dynamics in regeneration, development, and cancer.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"16 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524400","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":"Preservation of chondrocyte microspheroids by local sustained hydrogen supply improves osteoarthritic cartilage repair.","authors":"Shengqiang Chen,Mingrui Luo,Sizhen Chen,Danyang Chen,Lingting Zeng,Lina Shangguan,Zhengji Sun,Guanglin Li,Wenjiang Ding,Wei Tang,Qianjun He","doi":"10.1016/j.stem.2026.03.002","DOIUrl":"https://doi.org/10.1016/j.stem.2026.03.002","url":null,"abstract":"The inflammatory pathological microenvironment of osteoarthritis (OA) degrades the cell state and function of stem cell-derived grafts and presents a major obstacle to developing effective cell therapies. Here, we show that the viability and hyaline cartilage phenotype of bone marrow-derived mesenchymal stem cell (BMSC)-derived chondrocyte microspheroids (CMSs) can be efficiently preserved during spheroidization with persistent H2 supply and in an OA microenvironment. We therefore developed TiSi2 nanosheets (TSN) that hydrolytically generate a sustained (> 2 months) high dose of H2 and construct a H2-releasing hydrogel transplant (TSN/CMS-Gel) by encapsulating TSN and CMSs within a photo-crosslinking hydrogel (Gel). Transplantation of TSN/CMS-Gel achieves a strong survival of chondrocytes in a rodent OA model and promotes the rapid and efficient repair of sheep osteoarthritic critical-size cartilage defects, as well as the reversal of osteoarthritic progression within 6 months. The proposed strategy of locally sustaining H2-mediated preservation of transplanted chondrocytes in the pathological microenvironment opens new opportunities to enhance cell transplantation outcomes.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"2 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524604","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 : 2026-03-23DOI: 10.1016/j.stem.2026.02.011
Ashley N. Kamimae-Lanning, Jill M. Brown, Matthias Günther, Franziska Esau, Holly Russell, Lise Larcher, Frédéric Langevin, Tomoya Isobe, Nicola K. Wilson, Felix A. Dingler, Rebecca L. Cordell, Meng Wang, Christopher L. Millington, Nina Claudino, Ewa Gogola, Matthew Nicholls, Verena Körber, Berthold Göttgens, Marella F.T.R. de Bruijn, Juan I. Garaycoechea, Ketan J. Patel
{"title":"Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis","authors":"Ashley N. Kamimae-Lanning, Jill M. Brown, Matthias Günther, Franziska Esau, Holly Russell, Lise Larcher, Frédéric Langevin, Tomoya Isobe, Nicola K. Wilson, Felix A. Dingler, Rebecca L. Cordell, Meng Wang, Christopher L. Millington, Nina Claudino, Ewa Gogola, Matthew Nicholls, Verena Körber, Berthold Göttgens, Marella F.T.R. de Bruijn, Juan I. Garaycoechea, Ketan J. Patel","doi":"10.1016/j.stem.2026.02.011","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.011","url":null,"abstract":"DNA damage and mutations in hematopoietic stem cells (HSCs) enable clonal hematopoiesis (CH). Such damage occurs across a lifetime, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes HSC attrition and subsequently CH. We generated conditional mouse models lacking formaldehyde detoxification and Fanconi anemia (FA) DNA repair in blood. Formaldehyde protection was crucial for embryonic HSC emergence and throughout life. Despite severe deficiencies in HSCs, these mice produced blood for many months. To determine what enables this, we employed an unbiased method for detecting clones, which exploits somatic variant data. This revealed initial polyclonal hematopoiesis that diminishes to monoclonal hematopoiesis, devoid of known genetic selection. Furthermore, in FA children, we find the same transition to monoclonal hematopoiesis. Therefore, DNA damage-induced attrition down to the last functional cell can be a driving force for CH, representing an alternative route to CH other than purely by fitness-enhancing selection.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"16 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496067","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 : 2026-03-23DOI: 10.1016/j.stem.2026.02.010
Zhongqiu Li, Yanxin Li, Ziqing He, Changliang Wang, Yuehong Zhang, Rong Li, Lei Jin, Jin Jiao, Fen Ji, Bing Zhu, Jingjing Zhang, Peng Du, Ji Dong, Jianwei Jiao
{"title":"Decoding the spatiotemporal development of the blood-brain barrier in human cortex","authors":"Zhongqiu Li, Yanxin Li, Ziqing He, Changliang Wang, Yuehong Zhang, Rong Li, Lei Jin, Jin Jiao, Fen Ji, Bing Zhu, Jingjing Zhang, Peng Du, Ji Dong, Jianwei Jiao","doi":"10.1016/j.stem.2026.02.010","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.010","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501751","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":"Auditory activity sustains adult neurogenesis and cognition through the locus coeruleus-norepinephrine system.","authors":"Qiang Liu,Xing Luo,Ziqi Liang,Dezhe Qin,Min Wang,Weixiang Guo","doi":"10.1016/j.stem.2026.02.008","DOIUrl":"https://doi.org/10.1016/j.stem.2026.02.008","url":null,"abstract":"Hearing loss has been considered as potentially the leading modifiable risk factor for cognitive decline and dementia, but the causal link between these two conditions remains unsolved. Here, we report that mice with specific ablation of cochlear outer hair cells display marked hearing loss, which in turn leads to cognitive impairment and defective adult hippocampal neurogenesis. Furthermore, we discover that the dentate gyrus receives auditory input through a neuraxis, which originates from glutamatergic neurons of the caudal pontine reticular nucleus (PnCvGluT2) and relays via norepinephrinergic neurons of the locus coeruleus (LCNEergic). Hearing loss diminishes PnCvGluT2 to LCNEergic neuronal afferents, thereby reducing norepinephrine levels. Notably, stimulating PnCvGluT2 to LCNEergic neuronal afferents rescues the defective neurogenesis and cognitive impairment caused by hearing loss. Therefore, our study establishes a causal relationship between hearing loss and cognitive decline and emphasizes the importance of hearing wellness in sustaining cognitive function.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"32 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490063","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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