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}
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.
{"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}
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.
{"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}
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 in vivo, remains unexplored. Here, we report robust generation of non-β cells in vitro. 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.
{"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}
Pub Date : 2025-08-07DOI: 10.1016/j.stem.2025.07.005
Alperen Yilmaz, Gulben Gurhan, Mehmet-Yunus Comar, Sergey Viukov, Inbal Serfaty, Mert Gayretli, Sergey Golenchenko, Dmitry Lokshtanov, Shahd Ashouokhi, Angel Polanco, Idan Berlad, Tae-Won Ha, Alejandro Aguilera-Castrejon, Shadi Tarazi, Marina Cohen, Nir Livnat, Komal Kumar, Hisham Cholakkal, Nathan Levy, Nir Yosef, Jacob H. Hanna
The generation of post-gastrulation stem cell-derived mouse embryo models (SEMs) exclusively from naive embryonic stem cells (nESCs) has underscored their ability to give rise to embryonic and extra-embryonic lineages. However, existing protocols for mouse SEMs rely on the separate induction of extra-embryonic lineages and on ectopic expression of transcription factors to induce nESC differentiation into trophectoderm (TE) or primitive endoderm (PrE). Here, we demonstrate that mouse nESCs and naive induced pluripotent stem cells (niPSCs) can be simultaneously co-induced, via signaling pathway modulation, to generate PrE and TE extra-embryonic cells that self-organize into embryonic day (E) 8.5–E8.75 transgene-free (TF) SEMs. We also devised an alternative condition (AC) naive media that in vitro stabilizes TF-SEM-competent OCT4+/NANOG+ nESC colonies that co-express antagonistic CDX2 and/or GATA6 extra-embryonic fate master regulators and self-renew while remaining poised for TE and PrE differentiation, respectively. These findings improve mouse SEM strategies and shed light on amplifying an inherent and dormant extra-embryonic plasticity of mouse naive pluripotent cells in vitro.
{"title":"Transgene-free generation of mouse post-gastrulation whole embryo models solely from naive ESCs and iPSCs","authors":"Alperen Yilmaz, Gulben Gurhan, Mehmet-Yunus Comar, Sergey Viukov, Inbal Serfaty, Mert Gayretli, Sergey Golenchenko, Dmitry Lokshtanov, Shahd Ashouokhi, Angel Polanco, Idan Berlad, Tae-Won Ha, Alejandro Aguilera-Castrejon, Shadi Tarazi, Marina Cohen, Nir Livnat, Komal Kumar, Hisham Cholakkal, Nathan Levy, Nir Yosef, Jacob H. Hanna","doi":"10.1016/j.stem.2025.07.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.005","url":null,"abstract":"The generation of post-gastrulation stem cell-derived mouse embryo models (SEMs) exclusively from naive embryonic stem cells (nESCs) has underscored their ability to give rise to embryonic and extra-embryonic lineages. However, existing protocols for mouse SEMs rely on the separate induction of extra-embryonic lineages and on ectopic expression of transcription factors to induce nESC differentiation into trophectoderm (TE) or primitive endoderm (PrE). Here, we demonstrate that mouse nESCs and naive induced pluripotent stem cells (niPSCs) can be simultaneously co-induced, via signaling pathway modulation, to generate PrE and TE extra-embryonic cells that self-organize into embryonic day (E) 8.5–E8.75 transgene-free (TF) SEMs. We also devised an alternative condition (AC) naive media that <em>in vitro</em> stabilizes TF-SEM-competent OCT4+/NANOG+ nESC colonies that co-express antagonistic CDX2 and/or GATA6 extra-embryonic fate master regulators and self-renew while remaining poised for TE and PrE differentiation, respectively. These findings improve mouse SEM strategies and shed light on amplifying an inherent and dormant extra-embryonic plasticity of mouse naive pluripotent cells <em>in vitro</em>.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"9 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792325","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 : 2025-08-07DOI: 10.1016/j.stem.2025.07.001
Maria A. Telpoukhovskaia, Jennifer J. Trowbridge
While clonal hematopoiesis (CH) is associated with protection from Alzheimer’s disease (AD), a limited understanding of the mechanisms by which this occurs has been a barrier to therapeutic intervention. In a new study, Matatall et al.1 discover protective mechanisms by which TET2-mutant, but not DNMT3A-mutant, CH impacts dementia pathology and cognition.
{"title":"Plot twist: TET2 clones save the brain","authors":"Maria A. Telpoukhovskaia, Jennifer J. Trowbridge","doi":"10.1016/j.stem.2025.07.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.001","url":null,"abstract":"While clonal hematopoiesis (CH) is associated with protection from Alzheimer’s disease (AD), a limited understanding of the mechanisms by which this occurs has been a barrier to therapeutic intervention. In a new study, Matatall et al.<span><span><sup>1</sup></span></span> discover protective mechanisms by which <em>TET2</em>-mutant, but not <em>DNMT3A</em>-mutant, CH impacts dementia pathology and cognition.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"1 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792326","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 : 2025-08-07DOI: 10.1016/j.stem.2025.07.002
Danielle Klinger, Jeffrey A. Naftaly, Kristy Red-Horse
Gong et al. present a transcription factor-guided 3D differentiation that rapidly generates vascular organoids from human iPSCs, enhancing engraftment and revascularization of ischemic limbs and transplanted pancreatic islets in mouse models.1 This approach establishes a scalable platform for generating functional vasculature, supporting both disease modeling and regenerative therapy development.
{"title":"Vascular organoids get a speed boost for regenerative repair","authors":"Danielle Klinger, Jeffrey A. Naftaly, Kristy Red-Horse","doi":"10.1016/j.stem.2025.07.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.002","url":null,"abstract":"Gong et al. present a transcription factor-guided 3D differentiation that rapidly generates vascular organoids from human iPSCs, enhancing engraftment and revascularization of ischemic limbs and transplanted pancreatic islets in mouse models.<span><span><sup>1</sup></span></span> This approach establishes a scalable platform for generating functional vasculature, supporting both disease modeling and regenerative therapy development.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"6 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792324","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 : 2025-08-07DOI: 10.1016/j.stem.2025.06.011
Kewen Hu, Yajie Chen, Zhen Zhang
The poor survival of islets post-transplantation remains a significant challenge for type 1 diabetes mellitus (T1DM) therapy. Vandana et al.1 develop ChemPerturb-seq, which is integrated with in vivo barcoded screening to identify small molecule cocktails that enhance human beta cell and islet survival after transplantation, offering promising strategies for T1DM.
{"title":"Revolutionizing islet transplantation with a preconditioning boost for beta cell survival","authors":"Kewen Hu, Yajie Chen, Zhen Zhang","doi":"10.1016/j.stem.2025.06.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.06.011","url":null,"abstract":"The poor survival of islets post-transplantation remains a significant challenge for type 1 diabetes mellitus (T1DM) therapy. Vandana et al.<span><span><sup>1</sup></span></span> develop ChemPerturb-seq, which is integrated with <em>in vivo</em> barcoded screening to identify small molecule cocktails that enhance human beta cell and islet survival after transplantation, offering promising strategies for T1DM.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"52 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792336","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 : 2025-08-01DOI: 10.1016/j.stem.2025.07.011
Katie A. Matatall, Trisha K. Wathan, Minh Nguyen, Hu Chen, Alexandra McDonald, Guantong Qi, Julia A. Belk, Marcus A. Florez, Duy T. Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M. Buttigieg, Chih-wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E. Kennedy, Arushana A. Maknojia, Apoorva Thatavarty, Josaura V. Fernandez Sanchez, Hind Bouzid, Katherine Y. King
No Abstract
没有抽象的
{"title":"TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice","authors":"Katie A. Matatall, Trisha K. Wathan, Minh Nguyen, Hu Chen, Alexandra McDonald, Guantong Qi, Julia A. Belk, Marcus A. Florez, Duy T. Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M. Buttigieg, Chih-wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E. Kennedy, Arushana A. Maknojia, Apoorva Thatavarty, Josaura V. Fernandez Sanchez, Hind Bouzid, Katherine Y. King","doi":"10.1016/j.stem.2025.07.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.011","url":null,"abstract":"No Abstract","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"20 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756629","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 : 2025-07-30DOI: 10.1016/j.stem.2025.07.004
Guillermo C. Rivera-Gonzalez, Emily G. Butka, Carolynn E. Gonzalez, Rachel L. Mintz, Sarah S. Kleb, Violet Josephson, Wenjun Kong, Kunal Jindal, Kenji Kamimoto, Brett A. Shook, Matthew S. Rodeheffer, Samantha A. Morris
White adipose tissue supports essential physiological functions through adipocyte precursor cells (APCs), comprising progenitors and preadipocytes, which generate mature adipocytes during depot expansion. Using single-cell RNA sequencing-based lineage tracing, we characterize APCs in skin adipose tissue—a depot uniquely capable of rapid adipogenesis compared with other sites, such as inguinal adipose. We identify a previously uncharacterized population of immature preadipocytes and reveal distinct differentiation potentials among APCs. Contrary to traditional stepwise differentiation models, progenitors predominantly generate committed preadipocytes, whereas preexisting preadipocytes accumulate in immature states with divergent potential. Leveraging this refined APC hierarchy, we uncover Sox9 as a crucial regulator of progenitor proliferation and adipogenic differentiation. Cross-depot transplantation further demonstrates how intrinsic and extrinsic factors differentially regulate skin progenitor behavior, highlighting distinct adipogenic dynamics between skin and inguinal depots. Together, these insights redefine the cellular hierarchy and molecular mechanisms underpinning rapid adipogenesis in skin adipose tissue.
{"title":"Comparative single-cell lineage tracing identifies distinct adipocyte precursor dynamics in skin and inguinal fat","authors":"Guillermo C. Rivera-Gonzalez, Emily G. Butka, Carolynn E. Gonzalez, Rachel L. Mintz, Sarah S. Kleb, Violet Josephson, Wenjun Kong, Kunal Jindal, Kenji Kamimoto, Brett A. Shook, Matthew S. Rodeheffer, Samantha A. Morris","doi":"10.1016/j.stem.2025.07.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.07.004","url":null,"abstract":"White adipose tissue supports essential physiological functions through adipocyte precursor cells (APCs), comprising progenitors and preadipocytes, which generate mature adipocytes during depot expansion. Using single-cell RNA sequencing-based lineage tracing, we characterize APCs in skin adipose tissue—a depot uniquely capable of rapid adipogenesis compared with other sites, such as inguinal adipose. We identify a previously uncharacterized population of immature preadipocytes and reveal distinct differentiation potentials among APCs. Contrary to traditional stepwise differentiation models, progenitors predominantly generate committed preadipocytes, whereas preexisting preadipocytes accumulate in immature states with divergent potential. Leveraging this refined APC hierarchy, we uncover Sox9 as a crucial regulator of progenitor proliferation and adipogenic differentiation. Cross-depot transplantation further demonstrates how intrinsic and extrinsic factors differentially regulate skin progenitor behavior, highlighting distinct adipogenic dynamics between skin and inguinal depots. Together, these insights redefine the cellular hierarchy and molecular mechanisms underpinning rapid adipogenesis in skin adipose tissue.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"27 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737519","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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