Heart failure is the one of the leading causes of death in the United States. Myocardial infarction (MI) is followed by cardiac remodeling involving extensive fibrosis and which can ultimately progress into heart failure. Previous studies have shown both that both post-MI and post-ischemia reperfusion (I/R), there is a reduction in scar size and improved cardiac function as a result of administration of cortical bone stem cell (CBSC) treatment. We investigated the effects of mouse CBSCs (mCBSC), human CBSCs (hCBSC), mCBSC-derived exosomes and hCBSC-derived exosomes on murine embryonic fibroblast (MEF) migration. Exosome depletion from the CBSC-CM enhanced the reduction in fibroblast migration, implying exosome contents are involved in fibroblast migration. To examine if exosomes decrease fibrotic activation, adult rat ventricular fibroblasts (ARVFs) and adult human cardiac fibroblasts (NHCFs) were treated with TGFβ to activate fibrotic signaling before treatment with mCBSC- and hCBSC-derived exosomes. hCBSC-derived exosomes caused a 100-fold decrease in human fibroblast activation. To further understand the signaling mechanisms regulating the protective decrease in fibrosis, we performed RNA sequencing on the NHCFs after hCBSC-derived exosome treatment. The group treated with both TGFβ and exosomes showed a decrease in small nucleolar RNA (snoRNA), known to be involved with ribosome stability. A 24hr I/R study on mice showed that injection of mCBSCs and mCBSC-derived exosomes into the ischemic region of an infarct had a protective effect against I/R injury. Additionally, we found that mCBSC-derived exosomes recapitulate the effects of CBSC treatment post-I/R, indicating exosomes are partly responsible for CBSC's therapeutic effects.
