LAUSR

Background: Inflammatory mediators play important role in cardiac remodeling. In heart, fibrosis is mainly mediated by activated fibroblasts (myofibroblasts), however, origin of myofibroblasts in diseased heart remains unclear. Recently, we have shown that bone marrow fibroblast progenitor cells (FPCs) significantly contribute in cardiac fibrosis in IL10 KO (KO) mice, but its molecular mechanism is not known. Here, we hypothesize that BM-FPCs activate resident cardiac fibroblast via their paracrine mediators (packaged in exosomes) to exaggerate the cardiac fibrosis in KO mice post- transverse aortic constriction (TAC). Method and Results: Cardiac hypertrophy and fibrosis was induced in Wild-type (WT) and IL10-knockout (IL10KO) mice by TAC surgery. TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in KO mice. Recombinant IL10 administration markedly improved LV function and inhibited PO-induced cardiac fibrosis. PO enhanced FPC mobilization and homing in KO mice compared to WT mice. Furthermore, to identify the paracrine signaling, exosomes were isolated from WT and KO-FPCs culture media and characterized for fibrotic miRNA and proteins. Our data suggests that KO-FPC-exosomes are enriched with profibrotic miRs (miR21 and miR27) and proteins (RhoA). To explore whether KO-FPC-exosomes modulates resident fibroblasts biology and activation, adult cardiac fibroblasts (WT) were isolated and treated with WT and IL10KO-BMFPC-exosomes for 48 hrs. myoFB-associated gene (Collagen1α, Collagen3α and α- SMA) expression was notably increased in KO-FPC-exosome treated cells. Finally, immunostaining data further corroborated with our gene expression data and showed significantly enhanced α-SMA expression after KO-FPCs exosome treatments in cFBs. Conclusion: In conclusion, our data suggest that fibrotic remodeling factors (miRs and/or proteins) packaged in KO-FPC exosomes are sufficient to enhance the resident cardiac fibroblast activation and mediate cardiac fibrotic remodeling. Acknowledgement: NIH (RO1-135060) and AHA (14SDG20480104) SKV