Cell stem cellPub Date : 2026-03-05DOI: 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}
Cell stem cellPub Date : 2026-03-05DOI: 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}
Cell stem cellPub Date : 2026-02-25DOI: 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}
{"title":"Pluripotent stem cell-derived CAR-NK progenitor therapy targets minimal residual disease and prevents relapse in leukemia models","authors":"Zhiqian Wang, Leqiang Zhang, Dehao Huang, Chengxiang Xia, Qitong Weng, Yunqing Lin, Yanhong Liu, Zhenghan Liu, Ruowen Yi, Fan Zhang, Yaoqin Zhao, Jiaxin Wu, Hanmeng Qi, Lijuan Liu, Yiyuan Shen, Yi Chen, Yanping Zhu, Tongjie Wang, Mengyun Zhang, Fangxiao Hu, Jinyong Wang","doi":"10.1016/j.stem.2026.01.013","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.013","url":null,"abstract":"Reducing relapse rates post-chemotherapy remains a major challenge for improving cancer therapy. Here, we developed a pluripotent stem cell-derived induced natural killer (NK) lineage-committed progenitor (iNKP) cell therapy in leukemia models. We generated abundant iNKP cells via an organoid culture system. The iNKP cells, engineered to express C-X-C motif chemokine receptor 4 (CXCR4) and chimeric antigen receptors (CARs), efficiently migrated to the bone marrow and generated CAR-iNK cells, which persisted in multiple organs and peripheral blood for over 80 days. Notably, CAR-iNKP cell infusion precisely protected animals from tumor challenges. Furthermore, a single low-dose infusion of CAR-iNKP cells following conventional chemotherapy reduced minimal residual disease and significantly prevented cancer relapse in human CD19<sup>+</sup> B-ALL and CD7<sup>+</sup> T-ALL tumor-bearing animals. CAR-iNKP cell treatment addresses the limitations of traditional CAR-NK cell infusion and offers a new strategy for future application in human cancer therapy.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"31 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147278969","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 : 2026-02-23DOI: 10.1016/j.stem.2026.01.010
Yuqi Shen, Camelia Benlabiod, Edmund Watson, Kristian Gurashi, Alex Fower, Antonio Rodriguez-Romera, Jasmeet S. Reyat, Shady Adnan-Awad, Rupen Hargreaves, Samuel Kemble, Charlotte G. Smith, Adam P. Croft, Udo Oppermann, Alia Welsh, Lauren Murphy, Eleanor Murphy, Amirpasha Moetazedian, Natalie Jooss, Zoe C. Wong, Julie Rayes, Abdullah O. Khan
{"title":"comBO: A combined human bone and lympho-myeloid bone marrow organoid for preclinical modeling of hematopoietic disorders","authors":"Yuqi Shen, Camelia Benlabiod, Edmund Watson, Kristian Gurashi, Alex Fower, Antonio Rodriguez-Romera, Jasmeet S. Reyat, Shady Adnan-Awad, Rupen Hargreaves, Samuel Kemble, Charlotte G. Smith, Adam P. Croft, Udo Oppermann, Alia Welsh, Lauren Murphy, Eleanor Murphy, Amirpasha Moetazedian, Natalie Jooss, Zoe C. Wong, Julie Rayes, Abdullah O. Khan","doi":"10.1016/j.stem.2026.01.010","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.010","url":null,"abstract":"The bone marrow is the primary site of blood and immune cell production in postnatal life. Current human models do not capture lympho-myeloid hematopoiesis and the stromal diversity needed for lifelong blood and immune maintenance. Here, we introduce comBO (combined bone and lympho-myeloid bone marrow organoid), a scalable induced pluripotent stem cell (iPSC)-derived system that generates osteolineage, vascular, lymphoid, and myeloid compartments within a single organoid. Developed under physioxia in granular microgel scaffolds, comBOs improve scalability and reproducibility and sustain long-term lympho-myeloid potential in serial organoid re-seeding assays. Incorporating healthy or malignant donor cells produces “chimeroids” that model physiological and pathological states. Using multiple myeloma as an exemplar, comBOs recapitulate niche remodeling and identify macrophage inhibitory factor (MIF) signaling as a disease driver. MIF inhibition reduces inflammation and myeloma proliferation, highlighting its therapeutic potential. comBOs offer a physiologically faithful bone marrow platform for disease modeling and therapeutic discovery in translational hematology and immunology.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"13 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147278970","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 : 2026-02-23DOI: 10.1016/j.stem.2026.01.009
Chaoliang Li, Haohao Wang, Panrui Zhang, Jianbo Yang, Chao Ye, Xiaowei Wei, Yuchen Zhou, Zhentao Yang, Dan Cao, Kaiguang Zhang, Rongbin Zhou, Shu Zhu, Wen Pan
{"title":"VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis","authors":"Chaoliang Li, Haohao Wang, Panrui Zhang, Jianbo Yang, Chao Ye, Xiaowei Wei, Yuchen Zhou, Zhentao Yang, Dan Cao, Kaiguang Zhang, Rongbin Zhou, Shu Zhu, Wen Pan","doi":"10.1016/j.stem.2026.01.009","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.009","url":null,"abstract":"Intestinal stem cells (ISCs) drive epithelial renewal and regeneration, yet how neural cues shape ISC behavior remains unclear. Here, we identify a neuronal checkpoint that directly restrains ISC regenerative output during injury. We show that vasoactive intestinal peptide (VIP)-producing enteric neurons directly signal to ISCs through the epithelial receptor VIP receptor 1 (VIPR1). In steady state, VIP-VIPR1 signaling restrains ISC hyperproliferation by engaging an extracellular signal-regulated kinase (ERK)-Notum-Wnt/β-catenin inhibitory axis. During colitis, VIPergic neurons expand within the ulcerated regions and amplify this pathway, thereby suppressing ISC-driven regeneration and exacerbating epithelial injury. Selective deletion of <ce:italic>Vipr1</ce:italic> in the epithelium or in ISCs releases this neuronal brake, restores early regenerative activity, and markedly alleviates colitis. The ISC-suppressive function of VIP-VIPR1 signaling is conserved in human intestinal models. Together, these findings define VIPR1 as an ISC-intrinsic neuronal checkpoint that restricts ISC-driven epithelial regeneration and highlight epithelial VIPR1 blockade as a potential strategy to enhance mucosal regeneration in colitis.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"187 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147279228","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 : 2026-02-23DOI: 10.1016/j.stem.2026.01.008
Feiyu Yang, Narciso Pavon, Tatsuya Matsubara, Rebecca Sebastian, Beatriz Martinez-Martin, ChangHui Pak, Yubing Sun, Deok-Ho Kim
{"title":"Distinct spatial patterning and transcriptomic landscapes of human neural organoids by localized delivery of morphogens","authors":"Feiyu Yang, Narciso Pavon, Tatsuya Matsubara, Rebecca Sebastian, Beatriz Martinez-Martin, ChangHui Pak, Yubing Sun, Deok-Ho Kim","doi":"10.1016/j.stem.2026.01.008","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.008","url":null,"abstract":"Positional patterning during human brain development is orchestrated through highly coordinated interplays of locally produced inductive signals. Although animal models have elucidated general signaling pathways during early neurodevelopment, individual morphogens’ effects underlying the proper human brain regionalization remain unclear. Current technologies are limited in generating stable, well-confined gradients in neural organoids for robust regionalization. Here, we report a Matrigel-free passive diffusion-based morphogen gradient generator (PdMG) that reliably established a steep exogenous spatial morphogen gradient in human neural organoids. We further established dorsal-ventral forebrain, rostral-caudal fore-midbrain-like, and rostral-caudal fore-hindbrain-like patterning by applying Sonic hedgehog/Wingless/int1 (WNT) inhibitor, WNT, and retinoic acid gradients, respectively. Spatial transcriptomics analysis revealed robust regionalization in early-stage patterned organoids, as well as active neurogenesis and γ-aminobutyric acid (GABAergic) interneuron migrations in late-stage patterned organoids. Together, this study provides a framework for modeling the spatial-temporal morphogen dynamics that regulate key cell fate specifications and axis formations using patterned neural organoid models.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"6 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147279229","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 : 2026-01-27DOI: 10.1016/j.stem.2026.01.001
Dilem Ceren Apaydin, Gaurav Sadhnani, Tiffany Carlaw, Jan Renziehausen, Elena Lizunova, Viviane Filor, Anna Hiller, Sophia Brumhard, Vincent Halim, Ulrike Brüning, Johannes Bischof, Rafaela Horbach Marodin, Daniel Z. Kurek, Manuel Rhiel, Sandra Ammann, Tatjana I. Cornu, Toni Cathomen, Leif Erik Sander, Benedikt Obermayer, Fabian Coscia, Sarah Hedtrich
{"title":"Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models","authors":"Dilem Ceren Apaydin, Gaurav Sadhnani, Tiffany Carlaw, Jan Renziehausen, Elena Lizunova, Viviane Filor, Anna Hiller, Sophia Brumhard, Vincent Halim, Ulrike Brüning, Johannes Bischof, Rafaela Horbach Marodin, Daniel Z. Kurek, Manuel Rhiel, Sandra Ammann, Tatjana I. Cornu, Toni Cathomen, Leif Erik Sander, Benedikt Obermayer, Fabian Coscia, Sarah Hedtrich","doi":"10.1016/j.stem.2026.01.001","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.001","url":null,"abstract":"Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients’ quality of life and lack any effective treatment options. Here, we report clinically relevant <em>in situ</em> correction of the most common ARCI-causing mutation, <em>TGM1</em> c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of ∼30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of <em>in situ</em> gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"3 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057100","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 : 2026-01-21DOI: 10.1016/j.stem.2025.12.023
Rashmiparvathi Keshara, Karolina Kuodyte, Antje Janosch, Cordula Andree, Marc Bickle, Martin Stöter, Rico Barsacchi, Yung Hae Kim, Anne Grapin-Botton
{"title":"High-content screening of organoids reveals the mechanisms of human pancreas acinar specification","authors":"Rashmiparvathi Keshara, Karolina Kuodyte, Antje Janosch, Cordula Andree, Marc Bickle, Martin Stöter, Rico Barsacchi, Yung Hae Kim, Anne Grapin-Botton","doi":"10.1016/j.stem.2025.12.023","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.023","url":null,"abstract":"Organoids derived from pluripotent stem cells have emerged as powerful models to study human development. To investigate signaling pathways regulating human pancreas differentiation and morphogenesis, we developed a high-content, image-based screen and quantitative multivariate analysis pipelines robust to heterogeneity to extract single-cell and organoid features using pancreatic progenitor organoids. Here, we identified 54 compounds affecting cell identity and/or morphological landscape. Focusing on one family of compounds, we found that glycogen synthase kinase 3α/β (GSK3A/B) inhibition via wingless/int-1 (WNT) signaling has a reversible effect on cell identity, repressing pancreatic progenitor markers and inducing a poised state in progenitors transitioning to acinar cells. We show that additional fibroblast growth factor (FGF) repression enables further differentiation of acinar cells, recapitulating pancreatic acinar morphogenesis and function. The ability to produce acinar cells is valuable for future studies on pancreatic exocrine function and cancer initiation in humans, as acinar cells are thought to be an important cell of origin for pancreatic adenocarcinoma.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"69 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005601","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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