{"title":"Dynamic molecular atlas of cardiac fibrosis at single-cell resolution shows CD248 in cardiac fibroblasts orchestrates interactions with immune cells.","authors":"Guohua Li, Cheng Ni, Jiacheng Wang, Feimu Zhang, Zaiyang Fu, Lingjun Wang, Biqing Wang, Ye Liu, Jing Zhao, Mo Li, Hao Lin, Fei Liao, Shuchang Ye, Yu Zhang, Jiayue Cai, Shaohui Shi, Zhiwei Zhong, Yanna Shi, Junhua He, Xushen Xiong, Yang Xu, Jinghai Chen, Wei Zhu, Yibin Wang, Jian'an Wang, Xinyang Hu","doi":"10.1038/s44161-025-00617-1","DOIUrl":"https://doi.org/10.1038/s44161-025-00617-1","url":null,"abstract":"<p><p>Post-injury remodeling is a complex process involving temporal specific cellular interactions in the injured tissue where the resident fibroblasts play multiple roles. Here, we performed single-cell and spatial transcriptome analysis in human and mouse infarcted hearts to dissect the molecular basis of these interactions. We identified a unique fibroblast subset with high CD248 expression, strongly associated with extracellular matrix remodeling. Genetic Cd248 deletion in fibroblasts mitigated cardiac fibrosis and dysfunction following ischemia/reperfusion. Mechanistically, CD248 stabilizes type I transforming growth factor beta receptor and thus upregulates fibroblast ACKR3 expression, leading to enhanced T cell retention. This CD248-mediated fibroblast-T cell interaction is required to sustain fibroblast activation and scar expansion. Disrupting this interaction using monoclonal antibody or chimeric antigen receptor T cell reduces T cell infiltration and consequently ameliorates cardiac fibrosis and dysfunction. Our findings reveal a CD248<sup>+</sup> fibroblast subpopulation as a key regulator of immune-fibroblast cross-talk and a potential therapy to treat tissue fibrosis.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inflammatory CD248<sup>+</sup> activated fibroblasts are a potential therapeutic target in ischemic heart disease.","authors":"Joel G Rurik","doi":"10.1038/s44161-025-00632-2","DOIUrl":"https://doi.org/10.1038/s44161-025-00632-2","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"27-hydroxycholesterol and endothelial cell immune memory link maternal hypercholesterolemia with atherosclerosis in the offspring.","authors":"Chieko Mineo, Philip W Shaul","doi":"10.1038/s44161-025-00631-3","DOIUrl":"https://doi.org/10.1038/s44161-025-00631-3","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francis J A Leblanc, Chi Him Kendrick Yiu, Lucia M Moreira, Aaron M Johnston, Neelam Mehta, Antonios Kourliouros, Rana Sayeed, Stanley Nattel, Svetlana Reilly, Guillaume Lettre
{"title":"Single-nucleus multi-omics implicates androgen receptor signaling in cardiomyocytes and NR4A1 regulation in fibroblasts during atrial fibrillation.","authors":"Francis J A Leblanc, Chi Him Kendrick Yiu, Lucia M Moreira, Aaron M Johnston, Neelam Mehta, Antonios Kourliouros, Rana Sayeed, Stanley Nattel, Svetlana Reilly, Guillaume Lettre","doi":"10.1038/s44161-025-00626-0","DOIUrl":"https://doi.org/10.1038/s44161-025-00626-0","url":null,"abstract":"<p><p>The dysregulation of gene expression programs in the human atria during persistent atrial fibrillation (AF) is not completely understood. Here, we reanalyze bulk RNA-sequencing datasets from two studies (N = 242) and identified 755 differentially expressed genes in left atrial appendages of individuals with persistent AF and non-AF controls. We combined the bulk RNA-sequencing differentially expressed genes with a left atrial appendage single-nucleus multi-omics dataset to assign genes to specific atrial cell types. We found noncoding genes at the IFNG locus (LINC01479, IFNG-AS1) strongly dysregulated in cardiomyocytes. We defined a gene expression signature potentially driven by androgen receptor signaling in cardiomyocytes from individuals with AF. Cell-type-specific gene expression modules suggested an increase in T cell and a decrease in adipocyte and neuronal cell gene expression in AF. Lastly, we showed that reducing NR4A1 expression, a marker of a poorly characterized human atrial fibroblast subtype, fibroblast activation markers, extracellular matrix remodeling and cell proliferation decreased.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Manuel E Cantu Gutierrez, Matthew C Hill, Gabrielle E Largoza, William B Gillespie, James F Martin, Joshua D Wythe
{"title":"Mapping the transcriptional and epigenetic landscape of organotypic endothelial diversity in the developing and adult mouse.","authors":"Manuel E Cantu Gutierrez, Matthew C Hill, Gabrielle E Largoza, William B Gillespie, James F Martin, Joshua D Wythe","doi":"10.1038/s44161-025-00618-0","DOIUrl":"10.1038/s44161-025-00618-0","url":null,"abstract":"<p><p>The vascular endothelium features unique molecular and functional properties across different vessel types, such as between arteries, veins and capillaries, as well as between different organs, such as the leaky sinusoidal endothelium of the liver versus the impermeable vessels of the brain. However, the transcriptional networks governing endothelial organ specialization remain unclear. Here we profile the accessible chromatin and transcriptional landscapes of the endothelium from the mouse liver, lung, heart, kidney, brain and retina, across developmental time, to identify potential transcriptional regulators of endothelial heterogeneity. We then determine which of these putative regulators are conserved in human brain endothelial cells, and using single-cell transcriptomic profiling, we define which regulatory networks are active during brain maturation. Finally, we show that the putative transcriptional regulators identified by these three approaches molecularly and functionally reprogram naive endothelial cells. Thus, this resource can be used to identify potential transcriptional regulators controlling the establishment and maintenance of organ-specific endothelial specialization.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}