Single-cell RNA Sequencing for CD248 cKO Mouse hearts at myocardial infarction model
Post-injury remodeling is a complex process involving temporal specific cellular interactions in the injured tissue where the resident fibroblasts play multiple roles, including inflammation induction and tissue remodeling.   To dissect the molecular basis of these interactions, we performed single-cell and spatial transcriptome analysis in human and mouse hearts after myocardial infarction.  A subset of fibroblasts identified by unique high expression of CD248 was strongly correlated with collagen synthesis and remodeling, and genetic deletion of CD248 in fibroblast ameliorated cardiac fibrosis and dysfunction following ischemia/reperfusion, highlighting the functional importance of CD248 positive fibroblasts in post-injury pathological remodeling. CD248 stabilizes TGF-ßR ? protein and activates ACKR3 expression in fibroblast, leading to enhanced T cell adhesion and retention. This CD248 mediated fibroblast-T cell interaction is required to sustain fibroblast activation and scar expansion in injured heart. Disruption of this interaction using monoclonal antibody or Chimeric antigen receptor T cell reduces T cell infiltration, ameliorates ischemia/reperfusion-induced cardiac fibrosis and improves heart function.  Therefore, single cell molecular profiling in post-injury heart has uncovered a CD248 specific subclass of fibroblast with a critical role in fibroblast-T cell interaction and a new potential therapy to treat tissue fibrosis. Overall design: We generated fibroblast specific CD248 knockout mice by crossbreeding the Cd248fl/fl mice with the Postn-CreER mice, and then constructed cardiac myocardial infarction (MI) model. Cd248fl/fl littermate mice served as the control group.