Rationale Studies have demonstrated that exosomes can repair cardiac tissue post myocardial infarction (MI) and recapitulate the benefits of cellular therapy. Objective We evaluated the role of donor age and hypoxia of human pediatric cardiac progenitor cell (CPC)-derived exosomes, in a rat model of ischemia reperfusion (IR) injury. Methods and Results Human CPCs from the right atrial appendages from children of different ages undergoing cardiac surgery for congenital heart defects were isolated and cultured under hypoxic or normoxic conditions. Exosomes were isolated from the culture-conditioned media and delivered to athymic rats following IR injury. Echocardiography at day-3 post-MI suggested statistically improved function in neonatal hypoxic and neonatal normoxic groups compared to saline-treated controls. At 28 days post-MI exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia significantly improved cardiac function compared to saline-treated controls. Staining showed decreased fibrosis and improved angiogenesis in hypoxic groups compared to controls. Finally, using sequencing data, a computational model was generated to link microRNA levels to specific outcomes. Conclusion CPC exosomes derived from neonates improved cardiac function independent of culture oxygen levels, while CPC-exosomes from older children were not reparative unless subjected to hypoxic conditions. Cardiac functional improvements were associated with increased angiogenesis, reduced fibrosis and improved hypertrophy resulting in improved cardiac function; however, mechanisms for normoxic neonatal CPC exosomes improved function independent of those mechanisms. This is the first study of its kind demonstrating that donor age and oxygen content in the microenvironment significantly alter the efficacy of human CPC-derived exosomes.

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To investigate the role of age of human pediatric cardiac progenitor cells (hCPCs) on ventricular remodeling, the authors injected neonate, infant, or child hCPCs into rats with right ventricular heart failure. Mechanisms including migration and proliferation assays, as suggested by computational modeling, showed improved chemotactic and proliferative capacity of neonatal hCPCs compared with infant or child hCPCs. Thus, the reparative potential of hCPCs is age-dependent.