Pub Date : 2025-09-04DOI: 10.1016/j.stem.2025.07.013
Jessica Pham, Jane Isquith, Larisa Balaian, Shuvro P. Nandi, Claire Engstrom, Karla Mack, Inge van der Werf, Patrick Chang, Jana Stoudemire, Luisa Ladel, Emma Klacking, Antonio Ruiz, Daisy Chilin-Fuentes, Jenna Sneifer, David Mays, Paul Gamble, Shelby Giza, Jiya Janowitz, Trevor Nienaber, Tejaswini Mishra, Catriona H.M. Jamieson
Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.
{"title":"Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging","authors":"Jessica Pham, Jane Isquith, Larisa Balaian, Shuvro P. Nandi, Claire Engstrom, Karla Mack, Inge van der Werf, Patrick Chang, Jana Stoudemire, Luisa Ladel, Emma Klacking, Antonio Ruiz, Daisy Chilin-Fuentes, Jenna Sneifer, David Mays, Paul Gamble, Shelby Giza, Jiya Janowitz, Trevor Nienaber, Tejaswini Mishra, Catriona H.M. Jamieson","doi":"10.1016/j.stem.2025.07.013","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.013","url":null,"abstract":"Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"35 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987604","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}
Pub Date : 2025-09-04DOI: 10.1016/j.stem.2025.08.003
Jung-Won Shin, Maksim V. Plikus
Fat depots across the body dynamically tune their sizes in response to nutrient demands and nonmetabolic cues. Writing in Cell Stem Cell, Rivera-Gonzalez et al.1 report that skin fat, notable for its ability to rapidly expand, harbors molecularly distinct precursors, primed for proliferation and differentiation into mature adipocytes.
{"title":"Ready, set, but no go: Skin fat comes preloaded with waiting precursors","authors":"Jung-Won Shin, Maksim V. Plikus","doi":"10.1016/j.stem.2025.08.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.003","url":null,"abstract":"Fat depots across the body dynamically tune their sizes in response to nutrient demands and nonmetabolic cues. Writing in <em>Cell Stem Cell</em>, Rivera-Gonzalez et al.<span><span><sup>1</sup></span></span> report that skin fat, notable for its ability to rapidly expand, harbors molecularly distinct precursors, primed for proliferation and differentiation into mature adipocytes.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"15 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987602","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}
Pub Date : 2025-09-04DOI: 10.1016/j.stem.2025.08.007
Rossella Ventura
Dysfunction of A10 midbrain dopaminergic (mDA) neurons is linked to psychiatric disorders, such as depression. In this issue, Yan et al.1 present an efficient method for differentiating human pluripotent stem cells into A10-like mDA neurons. Activation of grafted A10-like neurons into the mouse mesolimbic circuit alleviates depression-like symptoms.
{"title":"Engineered VTA dopaminergic neurons offer a new path to treating depression","authors":"Rossella Ventura","doi":"10.1016/j.stem.2025.08.007","DOIUrl":"https://doi.org/10.1016/j.stem.2025.08.007","url":null,"abstract":"Dysfunction of A10 midbrain dopaminergic (mDA) neurons is linked to psychiatric disorders, such as depression. In this issue, Yan et al.<span><span><sup>1</sup></span></span> present an efficient method for differentiating human pluripotent stem cells into A10-like mDA neurons. Activation of grafted A10-like neurons into the mouse mesolimbic circuit alleviates depression-like symptoms.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"33 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987601","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}
Pub Date : 2025-09-04DOI: 10.1016/j.stem.2025.08.009
Roberto Castro-Gutierrez, Qizhi Tang
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.
{"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}
Pub 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
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 in vivo-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 (IC50) values across diverse human gastric cancer organoids resistant to first-line treatments. Mechanistically, gastric cancer organoids and in vivo tumors exhibit lipid metabolic adaptations not seen in two-dimensional (2D) in vitro 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.
{"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}
Pub Date : 2025-08-29DOI: 10.1016/j.stem.2025.08.005
Seiya Oura, Leijie Li, Jun Wu
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.
{"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}
Pub 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
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 in vivo 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.
{"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}
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.
{"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}
Pub 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
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 Cyp26b1-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 Cyp26b1 (talarozole) that prevents and rescues dermal fibrosis. Conclusively, we establish an atlas of the fibrotic and regenerative biological drivers of skin fibrosis.
{"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}
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 (TRAC) 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 de novo 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.
现成的CAR - T细胞需要可靠地逃脱同种异体免疫反应，才能成为通用药物。原代T细胞产物SC291通过CD19 CAR、T细胞受体α常数（TRAC）敲除、HLA缺失和CD47过表达的低免疫（HIP）编辑进行工程化。在这里，我们报告了来自hip -编辑CD19 CAR - T细胞的ARDENT （NCT05878184）和GLEAM （NCT06294236）试验的探索性免疫分析。尽管存在针对hla -充满的SC291亚群的同种免疫反应，但我们观察到，在所有患者中，无论剂量或患者的疾病如何，都没有针对完全编辑的HIP CAR - T细胞的新生免疫反应。缺乏针对hla -充满的CAR - T细胞的抗体被认为是深层组织CD19细胞耗竭的标志，所有60天没有这种抗体的患者外周血中都伴有B细胞耗竭。所提出的免疫数据支持HIP概念避免同种异体排斥反应的可靠性。
{"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}
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