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Transplantation of cardiosphere-derived cells (CDCs) has been shown to exert a therapeutic effect in patients with myocardial infarction (MI). However, poor survival of transplanted CDCs limits their beneficial effect. Metformin (MET) activates AMP-activated protein kinase (AMPK) which is associated with cell survival. This study is to determine whether MET improves CDC survival in the transplantation microenvironment and enhances the therapeutic effect of CDC transplantation against MI.
CDCs were isolated and expanded from transgenic b-actin-GFP mice. CDCs were pretreated with MET and intramyocardially injected into Wild-type C57 mouse heart with MI injury. The survival of CDCs was quantified, and the infarct size and cardiac function of treated hearts were evaluated.
CDC transplantation modestly reduced infarct size and improved cardiac function in post-MI heart, which was further improved by MET treatment. MET pretreatment significantly increased the survival of CDCs transplanted into myocardium. MET also reduced CDC apoptosis induced by oxidative stress in-vitro. The anti-apoptotic effect of MET was blocked by AMPK inhibitor compound C. MET increased AMPK phosphorylation and up-regulated endothelial nitric oxide synthase (eNOS) in CDCs under oxidative stress, which might be associated with the anti-apoptotic effect of MET.
MET improves the survival of transplanted CDCs in myocardium thereby enhancing their therapeutic effect against MI injury. The pro-survival function of MET on CDCs might be associated with an AMPK-eNOS dependent mechanism.