Cell stem cellPub Date : 2025-09-04DOI: 10.1016/j.stem.2025.08.009
Roberto Castro-Gutierrez, Qizhi Tang
{"title":"Face off: Stem cell therapy versus the immune system","authors":"Roberto Castro-Gutierrez, Qizhi Tang","doi":"10.1016/j.stem.2025.08.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.009","url":null,"abstract":"As stem cell therapies make great strides in clinical trials, the challenge of immune rejection has come into a sharper focus. Several recent clinical reports provide insight into the challenges posed by HLA mismatch and immunosuppression. Immunological analyses accompanying recent cell therapy trials suggest strategies that may mitigate these risks.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"16 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987608","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 : 2025-09-02DOI: 10.1016/j.stem.2025.08.006
Becky K.C. Chan, Chu Zhang, Chi Him Poon, Marie H.Y. Lee, Hoi Yee Chu, Bei Wang, Sin-Guang Chen, Helen H.N. Yan, Suet Yi Leung, Alan S.L. Wong
{"title":"A combined enteric neuron-gastric tumor organoid reveals metabolic vulnerabilities in gastric cancer","authors":"Becky K.C. Chan, Chu Zhang, Chi Him Poon, Marie H.Y. Lee, Hoi Yee Chu, Bei Wang, Sin-Guang Chen, Helen H.N. Yan, Suet Yi Leung, Alan S.L. Wong","doi":"10.1016/j.stem.2025.08.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.006","url":null,"abstract":"The discrepancy between organoid and immortalized cell line cultures for cancer target discovery remains unclear. Here, our multi-tiered clustered regularly interspaced short palindromic repeats (CRISPR) screens reveal <em>in vivo</em>-relevant metabolic dependencies and synthetic lethal pairs that can be uncovered with tumor organoids but not cell lines or even three-dimensional (3D) spheroids. These screens identify lanosterol synthase and acetyl-coenzyme A (CoA) carboxylase inhibitors as effective treatments that impede xenografted tumor growth in mice. These lipid metabolic inhibitors exhibit nanomolar half-maximal inhibitory concentration (IC<sub>50</sub>) values across diverse human gastric cancer organoids resistant to first-line treatments. Mechanistically, gastric cancer organoids and <em>in vivo</em> tumors exhibit lipid metabolic adaptations not seen in two-dimensional (2D) <em>in vitro</em> cultures. Additionally, enteric neurons modulate lipid metabolism in tumor organoids, altering drug sensitivity by up to two orders of magnitude. A neuron-cocultured CRISPR screen further reveals that acetyl-CoA carboxylase expression determines lanosterol synthase inhibitor efficacy. These findings highlight the critical roles of organoid environment and neuronal interaction in cancer lipid reliance.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"31 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928463","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 : 2025-08-29DOI: 10.1016/j.stem.2025.08.005
Seiya Oura, Leijie Li, Jun Wu
{"title":"An inducible model of human post-implantation development derived from primed and naive stem cells","authors":"Seiya Oura, Leijie Li, Jun Wu","doi":"10.1016/j.stem.2025.08.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.005","url":null,"abstract":"Early post-implantation human development is poorly understood due to limited access to natural embryos. Integrated stem cell-based embryo models (SCBEMs) offer an alternative, but current models face challenges in reproducibility, efficiency, and genomic stability. Here, we developed inducible SCBEMs (iSCBEMs) by combining primed human pluripotent stem cells (hPSCs) with transgene-induced extraembryonic cells derived from naive hPSCs. iSCBEMs recapitulate several key features of early post-implantation development, including amniotic-, yolk sac-, and chorionic-like cavity formation, differentiation of syncytiotrophoblast-like cells forming lacunae, bilaminar disk formation, anterior-posterior axis establishment, and early gastrulation. Single-cell RNA sequencing revealed that iSCBEMs recapitulate key cell types and developmental transitions characteristic of Carnegie stage 5–6 (CS5–CS6) embryos. We further traced the origins of amnion-, yolk sac endoderm-, and extraembryonic mesoderm-like cells, providing insights into their developmental trajectories. Although imperfect, human iSCBEMs represent a robust and valuable model for studying early post-implantation development, overcoming the limitations of natural embryo accessibility.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"29 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915965","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 : 2025-08-22DOI: 10.1016/j.stem.2025.07.014
Songbo Zhao, Rongkun Li, Yuan Xia, Xiaojie Wang, Zhiyong Liu, Qingqing Chu, Jiman He, Jiaying Zhang, Yixuan Guo, Youzhao Wang, Jichao Wu, Yan Zhang, Ziying Wang, Zhiyue Zhang, Rui Zeng, Chun Zhang, Jicheng Lv, Jinpeng Sun, Wei Tang, Fan Yi
{"title":"Targeting ECM-producing cells with CAR-T therapy alleviates fibrosis in chronic kidney disease","authors":"Songbo Zhao, Rongkun Li, Yuan Xia, Xiaojie Wang, Zhiyong Liu, Qingqing Chu, Jiman He, Jiaying Zhang, Yixuan Guo, Youzhao Wang, Jichao Wu, Yan Zhang, Ziying Wang, Zhiyue Zhang, Rui Zeng, Chun Zhang, Jicheng Lv, Jinpeng Sun, Wei Tang, Fan Yi","doi":"10.1016/j.stem.2025.07.014","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.014","url":null,"abstract":"Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, clinical interventions and therapies targeting kidney fibrosis remain conceptual and practical challenges due to the complex origin, functional heterogeneity, and regulation of scar-forming cells. Here, we define fibroblasts, pericytes, and myofibroblasts as the major extracellular matrix (ECM)-producing cells in the kidney, highlighting their primary contribution to kidney fibrosis. We then identify platelet-derived growth factor receptor β (PDGFRβ) as a potential targeting surface antigen for anti-fibrotic chimeric antigen receptor (CAR)-T against CKD. In multiple mouse CKD models, both adoptive transfer and CD5-lipid nanoparticle (LNP)-mediated <ce:italic>in vivo</ce:italic> generation of PDGFRβ CAR-T cells significantly ameliorate fibrosis-associated pathologies, including kidney, myocardial interstitial, and perivascular fibrosis without notable toxicity, evoking an integrated therapeutic strategy for multi-organ fibrosis in mice with CKD and its cardiovascular complications. The anti-fibrotic effects are also demonstrated in the human kidney organoid CKD, further strongly supporting the therapeutic potential for the treatment of patients with CKD.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"82 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900560","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":"Control of immune response in an iPSC-based allogeneic cell therapy clinical trial for Parkinson’s disease","authors":"Asuka Morizane, Emi Yamasaki, Takero Shindo, Takayuki Anazawa, Nobukatsu Sawamoto, Atsushi Shima, Hodaka Yamakado, Etsuro Nakanishi, Masanori Sawamura, Yosuke Taruno, Daisuke Doi, Tetsuhiro Kikuchi, Yuri Kawasaki, Megumu K. Saito, Takayuki Kikuchi, Yoshiki Arakawa, Susumu Miyamoto, Yuji Nakamoto, Ryosuke Takahashi, Jun Takahashi","doi":"10.1016/j.stem.2025.07.012","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.012","url":null,"abstract":"Because the central nervous system (CNS) is an immune-privileged organ, it requires different immunosuppression strategies for cell therapies using induced pluripotent stem cells (iPSCs) compared with ones for organ transplantations. We recently conducted the first in-human clinical trial of a cell therapy for Parkinson’s disease using allogeneic iPSCs (jRCT number: jRCT2090220384). All patients were transplanted with dopaminergic neural progenitors differentiated from iPSCs (iPSC-DANs), which had homozygous human leukocyte antigen (HLA) haplotypes, through immunosuppression with tacrolimus alone. No clinically significant immune reaction was observed in this study, regardless of HLA compatibility. However, a highly sensitive mixed lymphocyte reaction using iPSC-derived dendritic cells as a stimulator demonstrated the activation of lymphocytes from HLA-mismatch-grafted recipients. This finding suggests that the low expression of HLA in iPSC-DANs contributes to successful engraftment in the immune-privileged CNS. These results indicate that only moderate immunosuppressive treatment may be required for stem cell transplantation to the CNS.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"110 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900507","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 : 2025-08-14DOI: 10.1016/j.stem.2025.07.010
Michelle Griffin, Jason L. Guo, Jennifer B.L. Parker, Maxwell Kuhnert, Dayan J. Li, Caleb Valencia, Annah Morgan, Mauricio Downer, Asha C. Cotterell, John M. Lu, Sarah Dilorio, Khristian Eric Bauer-Rowe Ramos, Michael Januszyk, Howard Y. Chang, Derrick C. Wan, Michael T. Longaker
{"title":"Multi-omic analysis reveals retinoic acid molecular drivers for dermal fibrosis and regenerative repair in the skin","authors":"Michelle Griffin, Jason L. Guo, Jennifer B.L. Parker, Maxwell Kuhnert, Dayan J. Li, Caleb Valencia, Annah Morgan, Mauricio Downer, Asha C. Cotterell, John M. Lu, Sarah Dilorio, Khristian Eric Bauer-Rowe Ramos, Michael Januszyk, Howard Y. Chang, Derrick C. Wan, Michael T. Longaker","doi":"10.1016/j.stem.2025.07.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.010","url":null,"abstract":"Skin fibrosis is driven by fibroblast activation and excessive extracellular matrix deposition. To ascertain the fibroblast subpopulation(s) responsible for instigating fibrosis, we employed an established murine bleomycin skin fibrosis model. We characterized both the fibrotic and remodeling phases of dermal fibrosis through a multi-omic approach. Using an unsupervised machine learning algorithm that quantifies 294 fiber features, we identified precise time points of fibrosis and regeneration. Single-cell transcriptomic and epigenomic sequencing then identified a <em>Cyp26b1</em>-expressing fibroblast subpopulation responsible for dermal fibrosis. The same fibroblast subtype was mapped to Visium spatial transcriptomic data. We further mapped the fibrotic subtypes to protein spatial data. To ascertain the functional impact of the fibroblast subpopulations, transplant delivery analysis showed their ability to drive skin fibrosis. Lastly, we identified a small molecular inhibitor of <em>Cyp26b1</em> (talarozole) that prevents and rescues dermal fibrosis. Conclusively, we establish an atlas of the fibrotic and regenerative biological drivers of skin fibrosis.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"22 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840127","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":"Hypoimmune CD19 CAR T cells evade allorejection in patients with cancer and autoimmune disease","authors":"Xiaomeng Hu, Pascal Beauchesne, Chenyan Wang, Athena Wong, Tobias Deuse, Sonja Schrepfer","doi":"10.1016/j.stem.2025.07.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.009","url":null,"abstract":"Off-the-shelf CAR T cells need to reliably escape allogeneic immune responses to become universal medicines. The primary T cell product SC291 was engineered with a CD19 CAR, T cell receptor alpha constant (<em>TRAC</em>) knockout, and the hypoimmune (HIP) edits of HLA depletion and CD47 overexpression. Here, we report exploratory immune analyses from the ARDENT (NCT05878184) and GLEAM (NCT06294236) trials with HIP-edited CD19 CAR T cells. Although there was an alloimmune response against HLA-replete subpopulations of SC291, we observed no <em>de novo</em> immune response against fully edited HIP CAR T cells in all patients, irrespective of the dose or the patient’s disease. The lack of antibodies against the HLA-replete CAR T cells was identified as a marker for deep tissue CD19 cell depletion, and all patients without such antibodies for 60 days showed concomitant B cell depletion in peripheral blood. The immune data presented support the reliability of the HIP concept to evade allorejection.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"95 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825172","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":"A pancreatic cancer organoid biobank links multi-omics signatures to therapeutic response and clinical evaluation of statin combination therapy","authors":"Yunguang Li, Shijie Tang, Huan Wang, Hongwen Zhu, Yurun Lu, Yehan Zhang, Shiwei Guo, Juan He, Yikai Li, Yi Zhang, Xiaohan Shi, Yuanxiang Miao, Chaoliang Zhong, Yiqin Zhu, Yi Ju, Yuejia Liu, Maoyuan Sun, Yong Wang, Luonan Chen, Hu Zhou, Dong Gao","doi":"10.1016/j.stem.2025.07.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.008","url":null,"abstract":"Chemotherapy remains the primary treatment for pancreatic ductal adenocarcinoma (PDAC), but most patients ultimately develop resistance. Here, we established 260 pancreatic cancer organoid lines, followed by extensive multi-omics profiling and therapeutic sensitivity assessments. Integrated analyses uncovered 6 novel coding and 35 noncoding driver candidates. We discovered 2,794 multi-omics features associated with drug sensitivity and 322 features linked to radiation sensitivity. Pharmacogenomic analyses revealed that chemoresistant organoids exhibited enrichment in protein glycosylation and cholesterol metabolism pathways. Notably, statins effectively targeted chemoresistant PDAC organoids. Statin treatment attenuated protein glycosylation, cholesterol levels, and the epithelial-to-mesenchymal transition (EMT) signature in PDAC organoids. We conducted a single-center, single-arm, phase 2 clinical trial (NCT06241352) combining atorvastatin with chemotherapy in patients with advanced pancreatic cancer. Among 37 patients, 26 (70.3%) demonstrated a response, with tumor markers decreasing by more than 20%, suggesting durable responses and potential clinical benefits in this challenging patient population.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"23 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825265","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":"Human stem cell-derived A10 dopaminergic neurons specifically integrate into mouse circuits and improve depression-like behaviors","authors":"Wei Yan, Qinqin Gao, Yingying Zhou, Peibo Xu, Ziyan Wu, Tingli Yuan, Lianshun Xie, Zhiwen You, Xinyue Zhang, Ban Feng, Shanzheng Yang, Yuejun Chen, Man Xiong","doi":"10.1016/j.stem.2025.07.007","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.007","url":null,"abstract":"A10 dopaminergic neurons located in the ventral tegmental area play central roles in reward-related and goal-directed behaviors and are proposed to be target cells for treatment of various psychiatric disorders, including depression. Here, we report an efficient differentiation method to generate A10-like midbrain dopaminergic (mDA) neurons from human pluripotent stem cells (hPSCs) and found that post-mitotic patterning by Notch inhibitor, glial cell line-derived neurotrophic factor (GDNF), and ascorbic acid (AA) induced A10 subtype specification. These hPSC-derived mDA neurons exhibited characteristics of the A10 subtype, including gene expression profiles and electrophysiological properties. Moreover, grafted A10-like mDA neurons specifically project to their endogenous target brain regions and induce the anxiolytic phenotype in normal mice or antidepressant-like phenotypes in depression model mice. These results indicate that grafted A10-like mDA neurons can reconstruct specific circuits and functionally restore impaired circuits, highlighting the promising application of hPSC-derived neuron subtypes in the treatment of neuropsychiatric disorders.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"17 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813276","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":"Reconstruction of endocrine subtype-complete human pluripotent stem cell-derived islets with capacity for hypoglycemia protection in vivo","authors":"Gaofan Meng, Jiabin Gu, Soon Yi Liew, Jingxiao Cao, Zhihui Wang, Chunyu Ma, Zhenzhen Fu, Hongwen Zhou, Jinlin Wang, Shusen Wang, Sijia Jing, Yiqi Wu, Zhengjun Lei, Shuli Zhi, Yuanyuan He, Cheng Li, Hongkui Deng","doi":"10.1016/j.stem.2025.07.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.006","url":null,"abstract":"Transplantation of pluripotent stem cell-derived islets (PSC-islets), containing functional insulin-producing β cells, represents promising cell therapy for restoring glycemic control in diabetes. However, recapitulation of complete endocrine composition in PSC-islets remains challenging, and their ability to counteract hazardous hypoglycemia, crucial to metabolic safety <em>in vivo</em>, remains unexplored. Here, we report robust generation of non-β cells <em>in vitro</em>. By incorporating non-β and β cells, we report reconstruction of PSC-islets comprising all five (α, β, δ, ε, and γ) endocrine subtypes (reconstructed PSC-islets). After reversal of hyperglycemia in diabetic mouse models, these islets exhibited robust protection against hypoglycemia, with only 3% of measurements falling below 54 mg/dL compared with 59% in non-reconstructed controls. Remarkably, hypoglycemic clamp assays suggested restoration of previously defective counterregulatory response in reconstructed PSC-islet recipients. These findings establish a strategy to control relative abundance of PSC-islet subtypes, providing a basis for calibrating post-transplant glycemic homeostasis with definitive hypoglycemic protection.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"20 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797236","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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