Coronary artery disease can lead to myocardial infarction (MI), which is a major cause of morbidity and mortality in the US. Blockage of the coronary arteries prevents blood from reaching downstream target tissue, causing cardiomyocyte necrosis. This results in infarct expansion, dilation of the heart, scar formation, and depletion of cardiac pump function. Current therapies to restore blood flow to the affected tissue causes ischemia reperfusion (IR) injury which increases cardiomyocyte death and can lead to heart failure and mortality. Our lab has recently discovered a novel stem cell in the bone stroma, which we have called cortical bone stem cells (CBSCs). In both murine and porcine MI models, CBSCs were demonstrated to reduce scar size, promote cardioprotection of cardiomyocytes, induce new myocyte formation, and improve cardiac pump function post MI. Additionally, cardiomyocyte mass was shown to increase following CBSC treatment in pig MI/IR models at 3 months post MI. However, it is unclear if this increase in viable mass mainly results from protection of cardiomyocytes from death or the induction of myocyte growth from preexisting cardiomyocytes, rather than CBSCs. We will determine if CBSC secreted exosomes (CBSC-exo) are responsible for improving cardiac structure and function post MI/IR as seen with CBSC therapy. We will also define how CBSCs and/or their exosomes (CBSC-exo) directly protect adult cardiomyocytes from cell death, induce cardiomyocytes to reenter the cell cycle, and promote angiogenesis. For experimental studies, mice will undergo MI/IR surgery followed by injection of GFP+CBSCs, CBSC-exo, or saline. Cardiac repair will be assessed by echocardiography, invasive hemodynamics, histology and molecular studies to evaluate cardiac function, structural remodeling, cardiomyocyte density, and new blood vessel formation. To study the direct effects of CBSCs and their paracrine factors on myocytes and endothelial cells, adult feline cardiomyocytes or human endothelial cells will be subject to hypoxic damage and then treated with CBSCs, CBSC-exo, or CBSC cultured media. This proposed research should provide insight on how stem cells mediate cardiac repair through paracrine signaling. Results from these studies will determine whether exosomes can be used as a novel cell-free therapy to better repair the heart after MI/IR.
Coronary artery disease can lead to myocardial infarction (MI), causing cardiomyocyte necrosis and adverse cardiac remodeling and function. This proposed research will determine if exosomes secreted by cortical bone stem cells regulate cardiac repair post MI and examine their specific effects on cardiomyocyte survival, cardiac myogenesis, and angiogenesis. This study will define stem cell mediated repair mechanisms that can be used to enhance therapies for better repair of the heart following ischemia.
