Abstract
Although embryonic stem cells (ESCs) hold great promise for regeneration of the heart post myocardial infarction (MI) due to their pluripotent potential, it is this same potential that poses risk for the formation of teratomas. Lately there have been reports that exosomes, 30-100nm membrane bound vesicles, are not simply used by the cell to exocytose unwanted material, but contain intact protein, mRNA, and miRNA important for intercellular communication. Here we hypothesize that ESC derived exosomes can be used to exploit an already established mechanism to shuttle ESC content intercellularly in a cell free system for physiological and anatomical repair of the myocardium following acute myocardial infarction. To test our hypothesis exosomes were isolated by ultracentrifugation from equal numbers of murine ESCs or primary embryonic fibroblasts (MEFs). ESC exosomes had intact pluripotent transcripts similar to their parent cells in contrast the MEF exosomes. Using a double blinded acute myocardial infarction model, immediately after permanent ligation of the coronary artery, mice were injected with saline, ESC exosomes, or MEF exosomes at 3 locations in the border-zone of the left ventricle (LV). To assess the functional recovery of the LV, echocardiographical analysis was performed at Day 7, 14, and 28 following the AMI. Mice were sacrificed at D28 for histological assessments. LV fractional shortening, ejection fraction, and end systolic diameter measurements demonstrate that mice treated with ESC exosomes have improved LV function compared to mice treated with control MEF exosomes or saline alone (P<.05 for all functional parameters). Mice treated with ESC exosomes show less infarct size and apoptosis, greater capillary density, and greater cycling of both cardiomyocytes and ckit+ stem cells. Taken together, these data demonstrate a novel cell free system in which ESC exosomes can exploit regenerative capabilities of ESCs while bypassing the risk of teratoma formation and hold great promise for cardiovascular regenerative medicine.
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