{"title":"An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer","authors":"Kaiyi Li, Chang Liu, Xizhao Sui, Chao Li, Ting Zhang, Tian Zhao, Dong Zhang, Hainan Wu, Yuhan Liu, Shuai Wang, Yingshun Yang, Baobao Lin, Wenyan Wang, Fan Yang, Xiaofang Chen, Peng Liu","doi":"10.1016/j.stem.2025.05.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.011","url":null,"abstract":"Deciphering interactions between tumor micro- and systemic immune macroenvironments is essential for developing more effective cancer diagnosis and therapeutic strategies. Here, we established a gel-liquid interface (GLI) co-culture model of lung cancer organoids (LCOs) and paired peripheral-blood mononuclear cells (PBMCs), featuring enhanced interactions between immune cells and tumor organoids for optimized simulation of <em>in vivo</em> systemic anti-tumor immunity. By constructing a cohort of lung cancer patients, we demonstrated that the responses of GLI models under αPD1 treatment reflected the immunotherapy outcomes of the corresponding patients precisely. Furthermore, we dissected the various tumor immune processes mediated by PBMC-derived T cells within GLI models through functional multi-omics analyses, along with the characterization of circulating tumor-reactive T cells (GNLY<sup>+</sup>CD44<sup>+</sup>CD9<sup>+</sup>) with effector memory-like phenotypes as a potential indicator of immunotherapy efficacy. Our findings indicate that the GLI co-culture model can be used to develop diagnostic strategies for precision immunotherapies, as well as understanding the underlying mechanisms.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"100 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269214","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 : 2025-06-12DOI: 10.1016/j.stem.2025.05.013
Lin Lin, Carla Pou Casellas, Antonella F.M. Dost, Harry Begthel, Jeroen Korving, Stieneke van den Brink, Talya Dayton, Matthijs F.M. van Oosterhout, Niels Smakman, Lisa Thomann, Volker Thiel, Johan H. van Es, Hans Clevers
{"title":"Human airway submucosal gland organoids to study respiratory inflammation and infection","authors":"Lin Lin, Carla Pou Casellas, Antonella F.M. Dost, Harry Begthel, Jeroen Korving, Stieneke van den Brink, Talya Dayton, Matthijs F.M. van Oosterhout, Niels Smakman, Lisa Thomann, Volker Thiel, Johan H. van Es, Hans Clevers","doi":"10.1016/j.stem.2025.05.013","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.013","url":null,"abstract":"The human airway lining consists of two physiologically distinct compartments: the surface airway epithelium (SAE) and the submucosal glands (SMGs). Despite their critical role, the SMGs have remained largely overlooked in airway <em>in vitro</em> modeling of respiratory inflammation and infection. In this study, we leverage long-term cultured organoids derived separately from SAE and SMGs to investigate their unique physiological characteristics. Single-cell RNA sequencing (scRNA-seq) analysis confirms that these organoid models accurately replicate the cellular heterogeneity inherent to each tissue type. Specifically, SMG organoids are enriched in MUC5B-producing mucous cells and also generate alpha-smooth muscle actin (αSMA)-expressing myoepithelial cells. <em>ANPEP</em>/CD13 specifically marks SMG secretory cells. Exposure to cytokines elicits distinct inflammatory transcriptomic responses in SMG secretory cells. Infection assays with human alpha-coronavirus 229E (HCoV-229E) reveal the selective vulnerability of CD13-positive secretory cells, triggering an unfolded protein response. These findings broaden the utility of airway organoids for modeling respiratory (patho-)physiology.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"19 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269213","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 : 2025-06-05DOI: 10.1016/j.stem.2025.04.013
Harold M. McNamara, Berna Sozen
{"title":"From genes to geometry: Controlling embryo models by programming genomic activation","authors":"Harold M. McNamara, Berna Sozen","doi":"10.1016/j.stem.2025.04.013","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.013","url":null,"abstract":"Embryo-like models derived from stem cells have emerged as powerful tools to study early development. In this issue, Lodewijk et al.<span><span><sup>1</sup></span></span> demonstrate that activating just two enhancers via CRISPR activation (CRISPRa) in mouse embryonic stem cells (ESCs) can drive self-organization into structured embryo-like models, offering a genome-driven approach in stem cell and developmental biology.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"7 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219314","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 : 2025-06-05DOI: 10.1016/j.stem.2025.05.003
Jessica M. Thanos, John R. Lukens
{"title":"On-demand microglia deliver the therapeutic payload in Alzheimer’s disease","authors":"Jessica M. Thanos, John R. Lukens","doi":"10.1016/j.stem.2025.05.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.003","url":null,"abstract":"In this issue, Chadarevian et al. showed that engraftment of human iPSC-derived microglia (iMG) engineered to express secreted neprilysin (sNEP) under the plaque-responsive CD9 promoter reduces amyloid burden, neuronal damage, and inflammation in an Alzheimer’s disease (AD) mouse model.<span><span><sup>1</sup></span></span> These findings establish a cell-based strategy to treat neurological diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"9 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219315","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 : 2025-06-05DOI: 10.1016/j.stem.2025.05.008
Sowmya Viswanathan, Jacques Galipeau
{"title":"Hallmarks of MSCs: Key quality attributes for pharmacology and clinical use","authors":"Sowmya Viswanathan, Jacques Galipeau","doi":"10.1016/j.stem.2025.05.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.008","url":null,"abstract":"Marketing approval for allogenic mesenchymal stromal cells (MSCs) by international regulatory jurisdictions including the US have been granted. Notwithstanding, the long-heralded clinical and commercial breakthrough for MSC products has never fully manifested. The withdrawal of an allogenic MSC product in Europe, based on inefficacious phase 3 results along with setbacks in industry-sponsored, advanced clinical trials of MSCs for COVID-19-related acute respiratory distress syndrome (ARDS) have dampened enthusiasm for MSC products. In this perspective, we highlight the hallmarks of MSC identity and potency, and how these can inform surrogate, sensitive critical quality attributes that correlate with clinical effectiveness in a variety of indications. We further highlight host-dependent pharmacological attributes of MSCs, which together with their critical quality attributes drive the observed clinical responses and thus impact the translational utility of MSCs. We provide a rational pathway to additional MSC regulatory approval and deployment for disorders with unmet medical needs.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"39 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219120","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 : 2025-06-05DOI: 10.1016/j.stem.2025.05.010
Emilija Jovanovic, Fotios Sampaziotis
{"title":"Breathing new life into donor lungs: Theranostic methodology for organ repair","authors":"Emilija Jovanovic, Fotios Sampaziotis","doi":"10.1016/j.stem.2025.05.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.010","url":null,"abstract":"Recently in <em>Med</em>, Pinezich et al. present a therapeutic and diagnostic (“theranostic”) cross-circulation platform that enables prolonged, real-time rehabilitation of injured donor lungs <em>ex vivo</em>. Their approach integrating systemic support, advanced diagnostics, and targeted therapies promises to expand the donor lung pool and transform lung transplantation with personalized organ care.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"18 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219261","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 : 2025-06-05DOI: 10.1016/j.stem.2025.05.005
Young Cha, Pierre Leblanc, Kwang-Soo Kim
{"title":"A new era in regenerative medicine: Cell replacement therapy for Parkinson’s disease is on the horizon","authors":"Young Cha, Pierre Leblanc, Kwang-Soo Kim","doi":"10.1016/j.stem.2025.05.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.005","url":null,"abstract":"Parkinson’s disease (PD), characterized by the selective loss of midbrain dopaminergic neurons (mDANs), is a promising target for cell replacement therapy. Two recent clinical trials<span><span><sup>1</sup></span></span><sup>,</sup><span><span><sup>2</sup></span></span> published in <em>Nature</em> report the safety and potential efficacy of human pluripotent stem cell-based approaches, representing a major milestone in regenerative medicine for PD.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"456 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219219","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 : 2025-06-05DOI: 10.1016/j.stem.2025.05.006
Irene V. Choi, Rachel K. Zwick
{"title":"To play Paneth or goblet: Shapeshifting secretory cells read the room","authors":"Irene V. Choi, Rachel K. Zwick","doi":"10.1016/j.stem.2025.05.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.006","url":null,"abstract":"The intestinal secretory lineage is thought to comprise four distinct cell types derived from one Atoh1<sup>+</sup> progenitor, but the mechanisms that distinguish Paneth and goblet cells are unclear. Bhattacharya et al.<span><span><sup>1</sup></span></span> argue that these cells are instead phenotypic manifestations of a common terminal Atoh1<sup>+</sup> cell, actively shaped by niche-derived signals.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"12 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219218","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 : 2025-06-05DOI: 10.1016/j.stem.2025.05.009
Danilo Tagle
{"title":"Prioritizing human tissue research: Q&A with Danilo Tagle","authors":"Danilo Tagle","doi":"10.1016/j.stem.2025.05.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.009","url":null,"abstract":"Recently, the US National Institutes of Health (NIH) announced an initiative to expand human-based research technologies and minimize animal use in research. Danilo Tagle, Director of the Office for Special Initiatives at the National Center for Advancing Translational Sciences, shares his perspective on the upcoming changes with <em>Cell Stem Cell</em>.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"9 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219262","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 : 2025-06-05DOI: 10.1016/j.stem.2025.05.004
James Ellis, Knut Woltjen, Seema Mital, Megumu K. Saito, Akitsu Hotta, Jeanne F. Loring
{"title":"Diversifying the reference iPSC line concept","authors":"James Ellis, Knut Woltjen, Seema Mital, Megumu K. Saito, Akitsu Hotta, Jeanne F. Loring","doi":"10.1016/j.stem.2025.05.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.004","url":null,"abstract":"We discuss how to diversify the reference iPSC line concept. We highlight workflows for generating diverse iPSC lines. We ask whether reference lines can act as inclusive sources of human diversity for use in benchmarking controls for disease models or drug screens, or as clinical grade lines for cell therapies.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"31 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219293","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}