Abstract 428: Cortical Bone Stem Cell-derived Exosomes Reduce Myofibroblast Activation in Rat and Human Cardiac Fibroblasts

Abstract

Rationale: Heart failure is the one of the leading causes of death in the United States. Post-myocardial infarction is followed by cardiac remodeling that involves extensive fibrosis and ultimately progresses into heart failure. We have seen improvements in scar size and cardiac function as a result of administration of cortical bone stem cell-derived (CBSC) exosomes. Objectives: We investigated the mechanism through which CBSC-derived exosomes altered wound healing and reduced scar formation through in vitro experimentation. We continue to broaden our understanding of how CBSCs exert their anti-fibrotic effects. Methods and Results: We cultured adult rat ventricular fibroblasts and adult human cardiac fibroblasts and treated them +/- TGF β with mouse and human CBSC-derived exosomes, respectively. We saw a dose-dependent decrease in myofibroblast activation with increasing concentrations of mCBSC and hCBSC exosomes, with 100 fold decrease compared to baseline fibroblast activation in hCBSC treated cardiac fibroblasts (9.5 x 10 5 of 1.6 x 10 7 intensity), and by 40% in mCBSC treated cardiac fibroblasts (2.4 x 10 5 of 1.0 x 10 6 intensity). In the presence of TGFβ and 2.0 x 10 6 exosome particles/cell treated, the αSMA levels were still reduced by nearly 50% vs TGFβ alone (1.2 x 10 6 of 2.2 x 10 7 intensity). We performed RNA sequencing on both the rat and human cardiac fibroblasts in order to discover which fibrosis-related genes were being altered by CBSC exosomes treatment. Conclusions: Our findings show that the wound healing induced by CBSC exosome treatment post-MI involves the reduction of myofibroblast activation and decreasing the production of pro-fibrotic mRNA in cardiac fibroblasts and cardiac endothelial cells.