Experimental study of enhanced therapeutic effect of combining mesenchymal stem cell transplantation with erythropoietin in a myocardial infarction model

Objectives: To assess the effects on the changes of inflammatory cytokines of mesenchymal stem cell (MSC) transplantation combined with erythropoietin (EPO) administered during the acute period following myocardial infarction, as well as the therapeutic potency of the combined therapy, together with an investigation of the possible mechanisms involved. Methods: After the myocardial infarction models were established, 20 healthy Chinese swine were randomly divided into four groups: myocardial infarction (control) group, EPO group, MSC group and MSC + EPO group. MSC cells (1×107 cells) were implanted into the coronary artery (MSC and MSC-EPO groups). EPO (1,000 U/kg body weight) was administered subcutaneously by injection 3 times a week for 4 weeks (EPO and MSC-EPO groups). Control animals were injected with a saline solution during the same time period. In each group serum concentrations of TNF-α and IL-1β were detected at different time points following MI, and echocardiography was performed. Four weeks after cell transplantation, expressions of MMP-2 and MMP-9 proteins were assayed by immunohistochemistry and Western blot respectively, and capillary density was measured by immunohistochemistry. Results: Compared with other two groups, the concentration of TNF-α and IL-1β in the EPO group and MSC+MSC groups decreased markedly at different time points. When Compared with the control group, the following changes were observed in the EPO group and MSC+EPO group: LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD) and posterior wall thickness (PWT) decreased, LV ejection fraction (LVEF) increased, the expressions of MMP-2 and MMP-9 proteins were inhibited and capillary density was enhanced, but there were no differences between the MSC group and the control group. Furthermore, the benefit in the MSC+EPO group is more effective than that of the EPO group. Conclusions: EPO treatment can inhibit the inflammation response during the acute period following MI. A combination of MSC transplantation with EPO treatment during the acute period following MI results in better improvement of cardiac function and angiogenesis and the attenuation of left ventricular remodeling than either of the monotherapies. EPO enhances the beneficial effect of MSC transplantation, which may result from an inhibition of the inflammatory response.