Li Guohua, Ni Cheng, Wang Jiacheng, Zhang Feimu, Fu Zaiyang, Wang Lingjun, Wang Biqing, Liu Ye, Zhao Jing, Li Mo, Lin Hao, Liao Fei, Ye Shuchang, Zhang Yu, Cai Jiayue, Shi Shaohui, Zhong Zhiwei, Shi Yanna, He Junhua, Xiong Xushen, Xu Yang, Chen Jinghai, Zhu Wei, Wang Yibin, Wang Jian'an, Hu Xinyang
Department of Cardiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China.
Nat Cardiovasc Res. 2025 Apr;4(4):380-396. doi: 10.1038/s44161-025-00617-1. Epub 2025 Mar 27.
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 fibroblast subpopulation as a key regulator of immune-fibroblast cross-talk and a potential therapy to treat tissue fibrosis.
损伤后重塑是一个复杂的过程，涉及受损组织中特定时间的细胞相互作用，其中常驻成纤维细胞发挥多种作用。在这里，我们对人和小鼠梗死心脏进行了单细胞和空间转录组分析，以剖析这些相互作用的分子基础。我们鉴定出一个具有高CD248表达的独特成纤维细胞亚群，与细胞外基质重塑密切相关。成纤维细胞中Cd248基因缺失减轻了缺血/再灌注后的心脏纤维化和功能障碍。机制上，CD248稳定I型转化生长因子β受体，从而上调成纤维细胞ACKR3表达，导致T细胞滞留增加。这种CD248介导的成纤维细胞-T细胞相互作用是维持成纤维细胞活化和瘢痕扩展所必需的。使用单克隆抗体或嵌合抗原受体T细胞破坏这种相互作用可减少T细胞浸润，从而改善心脏纤维化和功能障碍。我们的研究结果揭示了一个CD248成纤维细胞亚群是免疫-成纤维细胞相互作用的关键调节因子，也是治疗组织纤维化的潜在疗法。
