Purified exosomes from human cardiac progenitor cells improve cardiac function after myocardial infarction in vivo

Background: Cardiac progenitor cell (CPC) transplantation improves cardiac function after myocardial infarction. Exosomes (Exo) are secreted nano-sized membrane vesicles that act as intercellular carriers of proteins and RNAs. Here, we investigated the role of Exo in the paracrine secretion by human CPCs (Exo-CPC), as compared to those from normal human fibroblasts (Exo-NHDF). Methods: CPC were derived from atrial explants of patients who underwent heart valve surgery. Exo were precipitated with ExoQuickTM. Cytoprotective and proangiogenic assays were performed with mouse cardiomyocytes (CM) and human endothelial cells (HUVEC), respectively. The in vivo effects of Exo- CPC and Exo-NHDF were tested in a rat model of acute myocardial infarction. Results: In vitro, Exo- CPC significantly reduced starvation-induced CM apoptosis by 59% (p<0.05), whereas Exo-NHDF did not. They also stimulated tube formation by HUVEC in Matrigel (total tube length 7912.38±1076 a.u.) compared with Exo-NHDF (total tube length 5095.25±747 a.u.; p<0.05). When injected into infarcted rat hearts, Exo-CPC, but not Exo-NHDF, significantly reduced infarct scar (0.58±0.08 a.u. vs. Exo-NHDF, 0.76±0.01 a.u.; p<0.05) while increasingnew vessel formation (84±13 vs. 34±5 vessels/mm2; p<0.01). Left ventricular ejection fraction decreased from baseline to 7 days in hearts injected with PBS (-21.3±4.5%) or Exo-NHDF (-12±6.3%) but was maintained in those injected with Exo-CPC (+0.8±6.8%; p<0.05 vs. PBS). Conclusions: Exo accounts for proangiogenic and antiapoptotic activities of human CPCs. Exo-CPC injected into infarcted hearts improves cardiac function early after MI. As a cell-free product, Exo-CPC has a potential for circumventing many of the limitations of cell therapy for cardiac repair.