Mechanisms of myocardial repair by cell-based therapy

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While it is well known that the implantation of bone marrow cells (BMCs) into ischemic hearts can induce angiogenesis and improve cardiac function after myocardial infarction, the precise mechanisms remain unclear. We tested the hypothesis that cytokines produced by BMCs play a key role in this cell-based therapy.BMCs from adult male Wistar rats were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions for 24 hours. ELISA and Western blotting analysis showed that various cytokines, including vascular endothelial growth factor, IL-1β, platelet-derived growth factor, and insulin-like growth factor 1, were produced from BMCs, and that some were enhanced significantly by hypoxia stimulation. Compared with a control blank medium, the supernatant of BMCs cultured under normoxic or hypoxic conditions significantly inhibited apoptosis (p<0.05), and increased the contractive function of isolated adult rat cardiomyocytes in vitro (p<0.05). Using a rat model of acute myocardial infarction, we injected the supernatant of BMCs or control medium intramyocardially on day 0, and then intraperitoneally on days 2, 4, and 6 after infarction. Compared with the control medium, administering the supernatant of BMCs cultured under both normoxic or hypoxic significantly increased the microvessel density and decreased the fibrotic area in the infarcted myocardium, which contributed to a significant improvement in cardiac function at days 7 after infarction (p<0.05).These results show that various cytokines were produced from BMCs, and these cytokines contributed to functional improvement of the infarcted heart, by directly protecting cardiomyocytes against ischemic injury, inducing therapeutic angiogenesis, and inhibiting remodeling of the infarcted heart.