Cell stem cellPub Date : 2026-07-02Epub Date: 2026-05-29DOI: 10.1016/j.stem.2026.05.001
Zhixin Kang, Hui Chen, Siyang Li, Shou-Wen Wang, Bin Zhou
{"title":"Evolving strategies for lineage tracing: Genetic markers, synthetic barcodes, and natural variants.","authors":"Zhixin Kang, Hui Chen, Siyang Li, Shou-Wen Wang, Bin Zhou","doi":"10.1016/j.stem.2026.05.001","DOIUrl":"10.1016/j.stem.2026.05.001","url":null,"abstract":"<p><p>Elucidating cell fate decision-making requires linking lineage history to dynamic phenotypic states. Driven by single-cell sequencing and genome engineering, lineage tracing has evolved from observational studies into a multidimensional, high-throughput discipline. Here, we synthesize its three methodological pillars: prospective tracking via genetic markers, high-throughput mapping using synthetic barcodes, and retrospective tracing leveraging endogenous natural variants. We survey their integration with multi-omics and spatial profiling, alongside computational approaches to decode cell fates from lineage data. By detailing each approach's trade-offs, we offer a systematic guide for experimental design and highlight emerging frontiers for translating precision clonal analysis into the clinic.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1066-1083"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148058869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-06-17DOI: 10.1016/j.stem.2026.05.006
Junfeng Ma, Lifu Zhu, Ping Duan, Tao Ding, Zhenghang Cheng, Bin Li, Qingfeng Wang, Xiang Ma, Youcai Deng, Deepak A Lamba, Yuan Gao
{"title":"Paired pre- and post-transplant human immunoprofiling identifies an IFN-γ-JAK1 axis limiting stem-cell-derived RPE engraftment.","authors":"Junfeng Ma, Lifu Zhu, Ping Duan, Tao Ding, Zhenghang Cheng, Bin Li, Qingfeng Wang, Xiang Ma, Youcai Deng, Deepak A Lamba, Yuan Gao","doi":"10.1016/j.stem.2026.05.006","DOIUrl":"10.1016/j.stem.2026.05.006","url":null,"abstract":"<p><p>Neovascular age-related macular degeneration is a major cause of irreversible blindness, and current therapies do not restore photoreceptors or retinal pigment epithelium (RPE). Human embryonic stem-cell-derived RPE (hESC-RPE) transplantation represents a potential regenerative strategy, but immune rejection limits durable engraftment. Here, we combine immune profiling of blood, aqueous humor, and retinal tissue with allogeneic co-cultures and humanized models to define determinants of graft vulnerability and assess a graft-directed intervention. We identify a Th1-skewed, IFN-γ-rich immune milieu across the circulation and eye and show that IFN-γ-JAK1 signaling promotes an immunogenic state in hESC-RPE, marked by increased HLA expression and antigen presentation features. Brief ex vivo conditioning with ruxolitinib attenuates this response while preserving epithelial properties. In humanized retinal degeneration models, conditioned grafts show reduced T/natural killer (NK)-cell infiltration, prolonged survival, and improved visual function without chronic systemic immunosuppression, supporting ex vivo JAK inhibition as a feasible adjunct to RPE cell therapy.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1127-1143.e10"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148274201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-06-08DOI: 10.1016/j.stem.2026.05.005
Zehra Abay-Nørgaard, Anika K Mueller, Erno Hänninen, Dylan Rausch, Louise Piilgaard, Lucía Sena Trujillo, Lorenzo Fedrizzi, Jens Bager Christensen, Alison Salvador, Alrik L Schörling, Noah Wulff Mottelson, Qiuyu Qin, Shruthi Sampath, Bob Hersbach, Jonas Henkenjohann, Sofie Peeters, Viktoriia Nikulina, Charlotte Høy Kruse, Yuan Li, Kavitha Chinnaiya, Marysia Placzek, Janko Kajtez, Tune H Pers, Agnete Kirkeby
{"title":"Generation of human appetite-regulating neurons and tanycytes from pluripotent stem cells.","authors":"Zehra Abay-Nørgaard, Anika K Mueller, Erno Hänninen, Dylan Rausch, Louise Piilgaard, Lucía Sena Trujillo, Lorenzo Fedrizzi, Jens Bager Christensen, Alison Salvador, Alrik L Schörling, Noah Wulff Mottelson, Qiuyu Qin, Shruthi Sampath, Bob Hersbach, Jonas Henkenjohann, Sofie Peeters, Viktoriia Nikulina, Charlotte Høy Kruse, Yuan Li, Kavitha Chinnaiya, Marysia Placzek, Janko Kajtez, Tune H Pers, Agnete Kirkeby","doi":"10.1016/j.stem.2026.05.005","DOIUrl":"10.1016/j.stem.2026.05.005","url":null,"abstract":"<p><p>The arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) are highly specialized hypothalamic nuclei controlling appetite and energy expenditure. Here, we demonstrate that human VMH and ARC neurons can be generated from pluripotent stem cells by fine-tuned timing and duration of bone morphogenetic protein (BMP) exposure. We identified SHH<sup>-</sup>/NKX2.1<sup>+</sup>/FGF10<sup>+</sup>/RAX<sup>+</sup>/TBX3<sup>+</sup> posterior tuberal progenitors as the source of ARC cell types, including agouti-related peptide (AGRP)-, prepronociceptin (PNOC)-, growth-hormone-releasing hormone (GHRH)-, and thyrotropin-releasing hormone (TRH)-expressing neurons and β2-tanycytes. Differentiated ARC cultures showed high transcriptomic similarity to human ARC and responded to energy homeostasis-regulatory peptides including leptin, glucagon-like peptide 1 (GLP-1), ghrelin, and fibroblast growth factor 1 (FGF1). In contrast, anterior tuberal TBX3<sup>-</sup> progenitors generated VMH-associated neurons expressing NR5A1, SOX14, and GPR149. Strikingly, two transcriptionally distinct pro-opiomelanocortin (POMC) subpopulations emerged from these lineages, mapping spatially to either the ARC (POMC<sup>+</sup>/TBX3<sup>+</sup>/NR5A2<sup>+</sup>) or the VMH (POMC<sup>+</sup>/SOX14<sup>+</sup>/NR5A1<sup>+</sup>). This model provides a cellular platform to study human hypothalamic subtype specification and pathways involved in central appetite regulation.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1174-1190.e11"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13353052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148207242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-06-16DOI: 10.1016/j.stem.2026.05.011
Lianjiu Su, Qihao Sun, Ziheng Zhou, Rending Wang, Junqiang Wang, Juan Felipe Alvarez, Bo Tao, Kiran Das, Qiuyuan Zhou, Jing Wang, Guanglin Zhang, Johanna Ten Hoeve, Linlin Zhang, Calvin Pan, Qiang Du, Hooman Allayee, Zhihao Liu, Ilya Savchenko, Shan Kou, Jijun Wan, Matteo Pellegrini, Aldons J Lusis, Thomas Graeber, Shen Li, Arjun Deb
{"title":"ENPP1 blockade with a humanized monoclonal antibody enhances renal repair after acute kidney injury.","authors":"Lianjiu Su, Qihao Sun, Ziheng Zhou, Rending Wang, Junqiang Wang, Juan Felipe Alvarez, Bo Tao, Kiran Das, Qiuyuan Zhou, Jing Wang, Guanglin Zhang, Johanna Ten Hoeve, Linlin Zhang, Calvin Pan, Qiang Du, Hooman Allayee, Zhihao Liu, Ilya Savchenko, Shan Kou, Jijun Wan, Matteo Pellegrini, Aldons J Lusis, Thomas Graeber, Shen Li, Arjun Deb","doi":"10.1016/j.stem.2026.05.011","DOIUrl":"10.1016/j.stem.2026.05.011","url":null,"abstract":"<p><p>The kidney possesses a poor ability to robustly regenerate and repair after acute injury. We show that the ectonucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase-1) is robustly expressed in diseased human kidneys and strongly correlates with clinical indices of renal dysfunction. Genetic targeting of Enpp1 in mice enhanced renal repair. A humanized monoclonal antibody, targeting human ENPP1 (hENPP1mAb), when administered in humanized mice, led to tubular cell proliferation, enhanced renal glomerular filtration rate, decreased fibrosis, and rescued renal function after kidney injury. hENPP1mAb augmented nucleotide metabolism and cellular energetics, enabling proliferation and rescuing cell cycle arrest. Single-cell transcriptomics demonstrated expanded signatures of effective repair with hENPP1mAb. In a good laboratory practice (GLP)-compliant dose escalation study, hENPP1mAb was found to be non-toxic and highly tolerated in non-human primates. Our findings identify ENPP1 as a central regulator of acute kidney injury and demonstrate the therapeutic benefit of targeting ENPP1 ectonucleotidase activity with a humanized monoclonal antibody.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1110-1126.e7"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148267262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-06-18DOI: 10.1016/j.stem.2026.05.007
James W Swann, Jun Hou Fung, Ziwei Chen, Oakley C Olson, Amélie Collins, Tenzin Lhakhang, Melissa A Proven, Ruiyuan Zhang, Raul Rabadan, Emmanuelle Passegué
{"title":"Quantitative molecular cartography of emergency myelopoiesis reveals conserved modules of hematopoietic activation.","authors":"James W Swann, Jun Hou Fung, Ziwei Chen, Oakley C Olson, Amélie Collins, Tenzin Lhakhang, Melissa A Proven, Ruiyuan Zhang, Raul Rabadan, Emmanuelle Passegué","doi":"10.1016/j.stem.2026.05.007","DOIUrl":"10.1016/j.stem.2026.05.007","url":null,"abstract":"<p><p>Hematopoietic stem and progenitor cells (HSPCs) respond to infections, inflammation, and regenerative challenges using emergency myelopoiesis (EM) pathways to amplify myeloid cell production. However, it remains unclear how various EM inducers regulate HSPCs using shared or distinct molecular mechanisms. Here, we generate a comprehensive and generalizable cell annotation method (HemaScribe) and a refined quantitative model of hematopoietic differentiation (HemaScape) using single-cell RNA sequencing (scRNA-seq) of murine HSPCs, which we apply to a broad range of EM modalities. We uncover multiple strategies for enhancing myelopoiesis that act at different levels of the HSPC hierarchy and are associated with both unique and shared transcriptional response modules. In particular, we identify a myeloid progenitor-based EM activation module across diverse inflammatory challenges that is conserved in humans and informs outcomes in adult and pediatric acute myeloid leukemia. Our work illuminates fundamental regulatory mechanisms in hematopoietic regeneration that have direct translational applications in disease contexts.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1223-1242.e14"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148280477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-05-25DOI: 10.1016/j.stem.2026.04.021
Woo Sub Yang, Mu Seog Choe, Cynthia Lo, Hui-Wen Liu, Yoon Mi Cho, Jonghun Kim, Ferdi Ridvan Kiral, Michael Scandura, Xiaona Lu, Kun-Yong Kim, Kyuhwan Na, Caihong Qiu, Fan Wu, Andrew Dirks, Rebecca Mathew, Bilal Cakir, Hyuk-Jin Cha, Sangwon F Kim, Andrew Cox, Seok Chung, Yong-Hui Jiang, Kunyoo Shin, Sang-Hun Lee, In-Hyun Park
{"title":"Human amygdala-like telencephalic organoids model stress circuitry in assembloid systems.","authors":"Woo Sub Yang, Mu Seog Choe, Cynthia Lo, Hui-Wen Liu, Yoon Mi Cho, Jonghun Kim, Ferdi Ridvan Kiral, Michael Scandura, Xiaona Lu, Kun-Yong Kim, Kyuhwan Na, Caihong Qiu, Fan Wu, Andrew Dirks, Rebecca Mathew, Bilal Cakir, Hyuk-Jin Cha, Sangwon F Kim, Andrew Cox, Seok Chung, Yong-Hui Jiang, Kunyoo Shin, Sang-Hun Lee, In-Hyun Park","doi":"10.1016/j.stem.2026.04.021","DOIUrl":"10.1016/j.stem.2026.04.021","url":null,"abstract":"<p><p>Human emotional and stress responses are orchestrated by subcortical limbic circuits, with the amygdala playing a central role in integrating affective, sensory, and endocrine signals. Despite the urgent need to understand how these circuits develop and contribute to anxiety and stress-related disorders, progress has been hindered by lack of ex vivo human models. Here, we generated human amygdala-like telencephalic organoids (hATOs) that recapitulate cellular composition, region-specific development, and key features of the amygdala. By assembling hATOs with a hypothalamic organoid (hypoTO) with paraventricular nucleus (PVN)-like features, we modeled the amygdala-hypothalamus-like interaction, which enabled circuit-level analysis of stress-responsive signaling. Exposure to cortisol led to robust upregulation of BCYRN1, a primate-specific retrotransposon-derived noncoding RNA, which uncovered a previously unrecognized mechanism of stress hormone signaling to retrotransposon biology and human-specific synaptic regulation. These findings highlight the potential of hATOs to understand molecular features of affective circuitry underlying emotion and the stress response and neuropsychiatric disorders.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1144-1160.e9"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148019370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-06-08DOI: 10.1016/j.stem.2026.05.004
Jonathan A Brassard, James M Wells
{"title":"Designing complex organoids through developmental principles.","authors":"Jonathan A Brassard, James M Wells","doi":"10.1016/j.stem.2026.05.004","DOIUrl":"10.1016/j.stem.2026.05.004","url":null,"abstract":"<p><p>Principles of developmental biology have inspired efforts for directed differentiation of human pluripotent stem cells (hPSCs), leading to the first generation of organoids that are now well established as models of human development and disease. However, first-generation organoid models were missing many cell types that would be needed to study normal and pathological processes. Here, we discuss how designing next-generation organoids with increased cellular complexity has been possible by better reproducing developmental processes in play during organogenesis in vivo. We focus on recent conceptual and technical advances in reconstructing appropriate cellular diversity in organoids, dissecting the importance of tissue-tissue interactions and specialized cell addition, and how engineering technologies can further enhance our ability to control how cells are brought together to mimic human development in vitro.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1084-1097"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148207022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-05-25DOI: 10.1016/j.stem.2026.04.016
Paul N Brennan, Alastair M Kilpatrick, Alison Glover, Lara Campana, Marc L Turner, Anne Elliott, Alexis Duncan, Neil J Lachlan, John F Dillon, Jonathan A Fallowfield, Stuart J Forbes
{"title":"Autologous macrophage therapy increases transplant-free survival in cirrhosis: Long-term follow-up of a phase 2 clinical trial.","authors":"Paul N Brennan, Alastair M Kilpatrick, Alison Glover, Lara Campana, Marc L Turner, Anne Elliott, Alexis Duncan, Neil J Lachlan, John F Dillon, Jonathan A Fallowfield, Stuart J Forbes","doi":"10.1016/j.stem.2026.04.016","DOIUrl":"10.1016/j.stem.2026.04.016","url":null,"abstract":"<p><p>Liver cirrhosis is a major contributor to global morbidity and mortality, and transplantation remains the only cure for end-stage disease. Preclinical studies have indicated that macrophage injections reduce inflammation, resolve fibrosis, and stimulate liver regeneration. The phase 1/2 Macrophage Therapy for Liver Cirrhosis trial (MATCH01; ISRCTN10368050) demonstrated the safety and potential efficacy of autologous monocyte-derived macrophage therapy in cirrhosis. Following MATCH01, participants were re-enrolled in a long-term follow-up (LTFU) study, extending observation to up to 4 years from randomization. Macrophage-treated patients in MATCH01 phase 2 demonstrated a significantly lower risk of death or transplant within the LTFU period (30.8%) compared with standard medical care (58.3%); macrophage-treated patients had an additional 252 days of restricted mean survival time within the LTFU period. There was no evidence of increased serious adverse events attributable to cell therapy. These results support the continued advancement of macrophage-based regenerative strategies as a promising therapeutic option for end-stage liver disease.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1098-1109.e3"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148019321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-05-25DOI: 10.1016/j.stem.2026.04.020
Yu Gong, Huiyu Zhu, Lingling Ge, Luoyan Wan, Simin Huang, Zhining Su, Mosaab Mohamed Elmahdi, Zhuang Xiong, Mingxia Ji, Qingqing Gou, Weihua Yu, Jiawen Li
{"title":"Human retinal organoids functionally bridge a transected optic nerve in a rat model.","authors":"Yu Gong, Huiyu Zhu, Lingling Ge, Luoyan Wan, Simin Huang, Zhining Su, Mosaab Mohamed Elmahdi, Zhuang Xiong, Mingxia Ji, Qingqing Gou, Weihua Yu, Jiawen Li","doi":"10.1016/j.stem.2026.04.020","DOIUrl":"10.1016/j.stem.2026.04.020","url":null,"abstract":"<p><p>Functional restoration of vision in adult mammals remains unattainable following complete transection of the optic nerve. In this study, we address this challenge by heterotopically transplanting human retinal organoids into the transection cavity of the optic nerve in adult rats. One month after transplantation, treated animals exhibited partial recovery of visual function, including a direct pupillary light reflex, visually evoked electrophysiological responses, and visually guided behaviors, which were sustained for at least 3 months. Neuroanatomical tracing and three-dimensional imaging revealed the formation of a structured host-graft coupling spanning the transection gap. Functional engagement of the graft was further supported by chemogenetic inhibition, which led to coordinated attenuation of visual function. Together, these findings provide proof of concept that heterotopic retinal organoid transplantation can establish a relay-like pathway supporting partial functional signal transmission across a completely transected optic nerve, offering an alternative conceptual framework for repairing severe optic nerve injuries.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1161-1173.e7"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148019351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-07-02Epub Date: 2026-06-16DOI: 10.1016/j.stem.2026.05.009
Sanjeeb Kumar Sahu, Sebastian Memczak, Sudhir Thakurela, Jinlong Lu, Priya Gupta, Naresh Mutukula, Alex Hirano, Yingzi Zhang, Tomoaki Hishida, Masakazu Kurita, Chao Wang, Yanjiao Shao, April Williams, Max Shokhirev, Vijay K Tiwari, Concepcion Rodriguez Esteban, Pradeep Reddy, Alexander Meissner, Mo Li, Juan Carlos Izpisua Belmonte
{"title":"ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.","authors":"Sanjeeb Kumar Sahu, Sebastian Memczak, Sudhir Thakurela, Jinlong Lu, Priya Gupta, Naresh Mutukula, Alex Hirano, Yingzi Zhang, Tomoaki Hishida, Masakazu Kurita, Chao Wang, Yanjiao Shao, April Williams, Max Shokhirev, Vijay K Tiwari, Concepcion Rodriguez Esteban, Pradeep Reddy, Alexander Meissner, Mo Li, Juan Carlos Izpisua Belmonte","doi":"10.1016/j.stem.2026.05.009","DOIUrl":"10.1016/j.stem.2026.05.009","url":null,"abstract":"<p><p>Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1191-1204.e10"},"PeriodicalIF":20.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148267285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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