Dilated cardiomyopathy (DCM) is considered as the final common response of myocardium to diverse genetic and environmental insults and characterized mainly by left ventricular systolic dysfunction. The current therapies for the treatment of DCM are costly high and outcomes are often unsatisfactory. To date, mesenchymal stem cells (MSCs) have been thought to be an ideal stem cell to repair damaged myocardium but was still within relatively small scales and few cases have been conducted in clinical trials. The use of erythropoietin (EPO), a growth factor produced in the kidneys have been found prevent cardiomyocyte apoptosis. This study was aimed to transplant MSCs into DCM rat bone marrow to express EPO in vivo and investigate the regulation of EPO on cell signaling pathways after transfection. The results found that transplantation of MSCs carrying EPO could significantly relief the cardiac dysfunctions of the DCM rat. This underylying mechanism involved with inhibiting p-NF-kappa B and p-P38, regulateing and promoting the anti-inflammatory balance, thereby alleviating tissue injury in DCM rats and exhibiting a protective role. Meanwhile, the MSCs + EPO treatment in DCM rat also activated the p-Akt pathway and thus protecting the myocardium from apoptosis in DCM rats. The study revealed an potential therapeutic effect of MSCs and EPO in clinical and provided a molecular mechanism of action for treating DCM. (C) 2019 The Authors. Published by Elsevier Inc.