Dynamic molecular atlas of cardiac fibrosis at single-cell resolution shows CD248 in cardiac fibroblasts orchestrates interactions with immune cells

Abstract

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. Using single-cell and spatial molecular profiling of infarcted mouse and human hearts, Li, Ni, Wang and colleagues identify a subset of cardiac fibroblasts expressing CD248 that plays a critical role in fibroblast–T cell interaction, and show that disrupting this interaction with monoclonal antibodies or anti-CD248 chimeric antigen receptor T cells results in reduced cardiac fibrosis and improved function.