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Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias 剪接因子突变白血病中错误剪接衍生的新抗原和同源tcr
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-23 DOI: 10.1016/j.cell.2025.03.047
Won Jun Kim, Edie I. Crosse, Emma De Neef, Inaki Etxeberria, Erich Y. Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X. Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H. Winick, Alexander M. Lewis, Robert F. Stanley, Omar Abdel-Wahab
{"title":"Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias","authors":"Won Jun Kim, Edie I. Crosse, Emma De Neef, Inaki Etxeberria, Erich Y. Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X. Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H. Winick, Alexander M. Lewis, Robert F. Stanley, Omar Abdel-Wahab","doi":"10.1016/j.cell.2025.03.047","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.047","url":null,"abstract":"Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8<sup>+</sup> T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in <em>CLK3</em> and <em>RHOT2</em> resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"43 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease PHGDH的转录调控驱动阿尔茨海默病的淀粉样蛋白病理
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-23 DOI: 10.1016/j.cell.2025.03.045
Junchen Chen, Fatemeh Hadi, Xingzhao Wen, Wenxin Zhao, Ming Xu, Shuanghong Xue, Pei Lin, Riccardo Calandrelli, John Lalith Charles Richard, Zhixuan Song, Jessica Li, Alborz Amani, Yang Liu, Xu Chen, Sheng Zhong
{"title":"Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease","authors":"Junchen Chen, Fatemeh Hadi, Xingzhao Wen, Wenxin Zhao, Ming Xu, Shuanghong Xue, Pei Lin, Riccardo Calandrelli, John Lalith Charles Richard, Zhixuan Song, Jessica Li, Alborz Amani, Yang Liu, Xu Chen, Sheng Zhong","doi":"10.1016/j.cell.2025.03.045","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.045","url":null,"abstract":"Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer’s disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity. PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology. A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH’s transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits. These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"4 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways 小鼠胚胎核组织的建立是由多种表观遗传途径精心策划的
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-23 DOI: 10.1016/j.cell.2025.03.044
Mrinmoy Pal, Tamas Schauer, Adam Burton, Tsunetoshi Nakatani, Federico Pecori, Alicia Hernández-Giménez, Iliya Nadelson, Marc A. Marti-Renom, Maria-Elena Torres-Padilla
{"title":"The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways","authors":"Mrinmoy Pal, Tamas Schauer, Adam Burton, Tsunetoshi Nakatani, Federico Pecori, Alicia Hernández-Giménez, Iliya Nadelson, Marc A. Marti-Renom, Maria-Elena Torres-Padilla","doi":"10.1016/j.cell.2025.03.044","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.044","url":null,"abstract":"The folding of the genome in the 3D nuclear space is fundamental for regulating all DNA-related processes. The association of the genome with the nuclear lamina into lamina-associated domains (LADs) represents the earliest feature of nuclear organization during development. Here, we performed a gain-of-function screen in mouse embryos to obtain mechanistic insights. We find that perturbations impacting histone H3 modifications, heterochromatin, and histone content are crucial for the establishment of nuclear architecture in zygotes and/or 2-cell-stage embryos. Notably, some perturbations exerted differential effects on zygotes versus 2-cell-stage embryos. Moreover, embryos with disrupted LADs can rebuild nuclear architecture at the 2-cell stage, indicating that the initial establishment of LADs in zygotes might be dispensable for early development. Our findings provide valuable insights into the functional interplay between chromatin and structural components of the nucleus that guide genome-lamina interactions during the earliest developmental stages.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"12 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A type 1 immune-stromal cell network mediates disease tolerance against intestinal infection 1型免疫基质细胞网络介导对肠道感染的疾病耐受
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-22 DOI: 10.1016/j.cell.2025.03.043
Susan Westfall, Maria E. Gentile, Tayla M. Olsen, Danielle Karo-Atar, Andrei Bogza, Franziska Röstel, Ryan D. Pardy, Giordano Mandato, Ghislaine Fontes, De’Broski Herbert, Heather J. Melichar, Valerie Abadie, Martin J. Richer, Donald C. Vinh, Joshua F.E. Koenig, Oliver J. Harrison, Maziar Divangahi, Sebastian Weis, Alex Gregorieff, Irah L. King
{"title":"A type 1 immune-stromal cell network mediates disease tolerance against intestinal infection","authors":"Susan Westfall, Maria E. Gentile, Tayla M. Olsen, Danielle Karo-Atar, Andrei Bogza, Franziska Röstel, Ryan D. Pardy, Giordano Mandato, Ghislaine Fontes, De’Broski Herbert, Heather J. Melichar, Valerie Abadie, Martin J. Richer, Donald C. Vinh, Joshua F.E. Koenig, Oliver J. Harrison, Maziar Divangahi, Sebastian Weis, Alex Gregorieff, Irah L. King","doi":"10.1016/j.cell.2025.03.043","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.043","url":null,"abstract":"Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here, we demonstrate that rapid induction of interferon γ (IFNγ) signaling coordinates a multicellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8<sup>+</sup> T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNγ acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNγ sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response did not impact parasite burden, indicating that IFNγ supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodeling.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"7 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Root microbiota regulates tiller number in rice 根系微生物群调控水稻分蘖数
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-22 DOI: 10.1016/j.cell.2025.03.033
Jingying Zhang, Bing Wang, Haoran Xu, Weidong Liu, Jingwei Yu, Qiuxia Wang, Hong Yu, Jin-Wei Wei, Rui Dai, Jinghang Zhou, Yuhang He, Di Zou, Jinhua Yang, Xinwei Ban, Qingliang Hu, Xiangbing Meng, Yong-Xin Liu, Binglei Wang, Bin Hu, Mingyu Wang, Yang Bai
{"title":"Root microbiota regulates tiller number in rice","authors":"Jingying Zhang, Bing Wang, Haoran Xu, Weidong Liu, Jingwei Yu, Qiuxia Wang, Hong Yu, Jin-Wei Wei, Rui Dai, Jinghang Zhou, Yuhang He, Di Zou, Jinhua Yang, Xinwei Ban, Qingliang Hu, Xiangbing Meng, Yong-Xin Liu, Binglei Wang, Bin Hu, Mingyu Wang, Yang Bai","doi":"10.1016/j.cell.2025.03.033","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.033","url":null,"abstract":"Rice tillering is an important agronomic trait regulated by plant genetic and environmental factors. However, the role and mechanism of the root microbiota in modulating rice tillering have not been explored. Here, we examined the root microbiota composition and tiller numbers of 182 genome-sequenced rice varieties grown under field conditions and uncovered a significant correlation between root microbiota composition and rice tiller number. Using cultivated bacterial isolates, we demonstrated that various members of the root microbiota can regulate rice tillering in both laboratory and field conditions. Genetic, biochemical, and structural analyses revealed that cyclo(Leu-Pro), produced by the tiller-inhibiting bacterium <em>Exiguobacterium</em> R2567, activates the rice strigolactone (SL) signaling pathway by binding to the SL receptor OsD14, thus regulating tillering. The present work provides insight into how the root microbiota regulates key agronomic traits and offers a promising strategy for optimizing crop growth by harnessing the root microbiota in sustainable agriculture.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"12 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tissue geometry spatiotemporally drives bacterial infections 组织几何在时空上驱动细菌感染
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-21 DOI: 10.1016/j.cell.2025.03.042
Yiming Han, Xiaoye Liu, Shaoqi Qu, Xiaocen Duan, Yunqing Xiang, Nan Jiang, Shuyu Yang, Xu Fang, Liang Xu, Hui Wen, Yue Yu, Shuqiang Huang, Jianyong Huang, Kui Zhu
{"title":"Tissue geometry spatiotemporally drives bacterial infections","authors":"Yiming Han, Xiaoye Liu, Shaoqi Qu, Xiaocen Duan, Yunqing Xiang, Nan Jiang, Shuyu Yang, Xu Fang, Liang Xu, Hui Wen, Yue Yu, Shuqiang Huang, Jianyong Huang, Kui Zhu","doi":"10.1016/j.cell.2025.03.042","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.042","url":null,"abstract":"Epithelial tissues serve as the first line of host against bacterial infections. The self-organization of epithelial tissues continuously adapts to the architecture and mechanics of microenvironments, thereby dynamically impacting the initial niche of infections. However, the mechanism by which tissue geometry regulates bacterial infection remains poorly understood. Here, we showed geometry-guided infection patterns of bacteria in epithelial tissues using bioengineering strategies. We discovered that cellular traction forces play a crucial role in the regulation of bacterial invasive sites and marginal infection patterns in epithelial monolayers through triggering co-localization of mechanosensitive ion channel protein Piezo1 with bacteria. Further, we developed precise mechanobiology-based strategies to potentiate the antibacterial efficacy in animal models of wound and intestinal infection. Our findings demonstrate that tissue geometry exerts a key impact on mediating spatiotemporal infections of bacteria, which has important implications for the discovery and development of alternative strategies against bacterial infections.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"125 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A cognitive map for value-guided choice in the ventromedial prefrontal cortex 腹内侧前额叶皮层价值导向选择的认知图
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-21 DOI: 10.1016/j.cell.2025.03.038
Sebastijan Veselic, Timothy H. Muller, Elena Gutierrez, Timothy E.J. Behrens, Laurence T. Hunt, James L. Butler, Steven W. Kennerley
{"title":"A cognitive map for value-guided choice in the ventromedial prefrontal cortex","authors":"Sebastijan Veselic, Timothy H. Muller, Elena Gutierrez, Timothy E.J. Behrens, Laurence T. Hunt, James L. Butler, Steven W. Kennerley","doi":"10.1016/j.cell.2025.03.038","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.038","url":null,"abstract":"The prefrontal cortex (PFC) is crucial for economic decision-making. However, how PFC value representations facilitate flexible decisions remains unknown. We reframe economic decision-making as a navigation process through a cognitive map of choice values. We found rhesus macaques represented choices as navigation trajectories in a value space using a grid-like code. This occurred in ventromedial PFC (vmPFC) local field potential theta frequency across two datasets. vmPFC neurons deployed the same grid-like code and encoded chosen value. However, both signals depended on theta phase: occurring on theta troughs but on separate theta cycles. Finally, we found sharp-wave ripples—a key signature of planning and flexible behavior—in vmPFC. Thus, vmPFC utilizes cognitive map-based computations to organize and compare values, suggesting an alternative architecture for economic choice in PFC.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"23 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Red blood cells undergo lytic programmed cell death involving NLRP3 红细胞发生与NLRP3相关的溶解性程序性细胞死亡
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-18 DOI: 10.1016/j.cell.2025.03.039
Yaozhen Chen, Shouwen Chen, Zhixin Liu, Yafen Wang, Ning An, Yutong Chen, Yihao Peng, Zheng Liu, Qin Liu, Xingbin Hu
{"title":"Red blood cells undergo lytic programmed cell death involving NLRP3","authors":"Yaozhen Chen, Shouwen Chen, Zhixin Liu, Yafen Wang, Ning An, Yutong Chen, Yihao Peng, Zheng Liu, Qin Liu, Xingbin Hu","doi":"10.1016/j.cell.2025.03.039","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.039","url":null,"abstract":"The canonical complement-mediated lysis of mature red blood cells (RBCs) leads to severe pathogenesis. However, inhibition strategies targeting complement are not always as efficient as expected, indicating that unknown mechanisms are awaiting elucidation. In this study, we investigate the intracellular events in mature RBCs following complement activation. The collected evidence demonstrates that complement-induced hemolysis is a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs are identified to engage in the assembly of NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC)-caspase-8 complex. Activated caspase-8 directly induces the proteolysis of β-spectrin, thereby disrupting the skeletal network of the RBC membrane, a process we refer to as spectosis. Spectosis signaling is also activated in autoimmune hemolytic anemia or paroxysmal nocturnal hemoglobinuria, and the inhibition of spectosis significantly reduced complement-induced hemolysis. These findings reveal a programmed death cascade in mature RBCs, which may have important implications for the treatment of hemolytic disorders.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CD36-mediated endocytosis of proteolysis-targeting chimeras 靶向蛋白水解嵌合体cd36介导的内吞作用
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-17 DOI: 10.1016/j.cell.2025.03.036
Zhengyu Wang, Bo-Syong Pan, Rajesh Kumar Manne, Jungang Chen, Dongwen Lv, Minmin Wang, Phuc Tran, Tsigereda Weldemichael, Wei Yan, Hongfei Zhou, Gloria M. Martinez, Jingwei Shao, Che-Chia Hsu, Robert Hromas, Daohong Zhou, Zhiqiang Qin, Hui-Kuan Lin, Hong-Yu Li
{"title":"CD36-mediated endocytosis of proteolysis-targeting chimeras","authors":"Zhengyu Wang, Bo-Syong Pan, Rajesh Kumar Manne, Jungang Chen, Dongwen Lv, Minmin Wang, Phuc Tran, Tsigereda Weldemichael, Wei Yan, Hongfei Zhou, Gloria M. Martinez, Jingwei Shao, Che-Chia Hsu, Robert Hromas, Daohong Zhou, Zhiqiang Qin, Hui-Kuan Lin, Hong-Yu Li","doi":"10.1016/j.cell.2025.03.036","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.036","url":null,"abstract":"Passive diffusion does not explain why many drugs are too large and/or too polar for rule-breaking membrane penetration, such as proteolysis-targeting chimeras (PROTACs, generally of a molecular weight &gt; 800 Da). Here, using biotinylated chemical-probe-based target fishing and genetic knockdown/knockin approaches, we discovered that the membrane cluster of differentiation 36 (CD36) binds to and facilitates the uptake and efficacy of diverse PROTACs (e.g., SIM1-Me, MZ1, and clinical ARV-110) and large and/or polar small-molecule drugs (e.g., rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin) via the CD36-mediated early endosome antigen 1 (EEA1)/Ras-related protein 5A (Rab5) endosomal cascade <em>in vitro</em> and/or <em>in vivo</em>. We then devised a novel chemical endocytic medicinal chemistry strategy to improve binding of PROTACs to CD36 using structural modifications via the prodrug approach, markedly enhancing PROTAC anti-tumor efficacy through spontaneously augmenting permeability and solubility.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fate and state transitions during human blood vessel organoid development 人体血管类器官发育过程中的命运和状态转换
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-17 DOI: 10.1016/j.cell.2025.03.037
Marina T. Nikolova, Zhisong He, Makiko Seimiya, Gustav Jonsson, Wuji Cao, Ryo Okuda, Reiner A. Wimmer, Ryoko Okamoto, Josef M. Penninger, J. Gray Camp, Barbara Treutlein
{"title":"Fate and state transitions during human blood vessel organoid development","authors":"Marina T. Nikolova, Zhisong He, Makiko Seimiya, Gustav Jonsson, Wuji Cao, Ryo Okuda, Reiner A. Wimmer, Ryoko Okamoto, Josef M. Penninger, J. Gray Camp, Barbara Treutlein","doi":"10.1016/j.cell.2025.03.037","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.037","url":null,"abstract":"Human blood vessel organoids (hBVOs) have emerged as a system to model human vascular development and disease. Here, we use single-cell multi-omics together with genetic and signaling pathway perturbations to reconstruct hBVO development. Mesodermal progenitors bifurcate into endothelial and mural fates <em>in vitro</em>, and xenografted BVOs acquire definitive arteriovenous endothelial cell specification. We infer a gene regulatory network and use single-cell genetic perturbations to identify transcription factors (TFs) and receptors involved in cell fate specification, including a role for MECOM in endothelial and mural specification. We assess the potential of BVOs to generate organotypic states, identify TFs lacking expression in hBVOs, and find that induced LEF1 overexpression increases brain vasculature specificity. Finally, we map vascular disease-associated genes to hBVO cell states and analyze an hBVO model of diabetes. Altogether, we provide a comprehensive cell state atlas of hBVO development and illuminate the power and limitation of hBVOs for translational research.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"66 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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