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Our previous study demonstrated that apelin level increased significantly after the treatment of intracoronary implantation of bone marrow mononuclear cells (BMMCs), followed by the improvement of cardiac function in patients with severe ischemic heart failure. The present studies both in vivo and in vitro explored whether mesenchymal stem cells derived from bone marrow (BMSCs) activate the apelin-APJ pathway when differentiating into cardiomyogenic cells. Isolated BMSCs from rat femurs and tibias were cultured and expanded for three passages, labeled with DAPI, and treated with 5-azacytidine (5-AZ). BMSCs labeled with ad-EGFP were injected intramyocardially into the peri-infarct area of rat models with acute myocardial infarction. Immunofluorescence staining exposed that CMGs expressed apelin together with myogenic-specific proteins such as α-actin, troponin T, GATA-4, and connexin-43 at 7 days after 5-AZ treatment or EGFP-BMSC injection. RT-PCR revealed that mRNA in CMGs started to express apelin and APJ from day 7 and progressively increased until day 28. Cardiac function, as measured by echocardiography in vivo, was significantly improved in parallel with the extent of apelin expression after BMSC transplantation. Our finding indicated that the expression of the apelin-APJ pathway during differentiation of BMSCs into CMGs may be an important mechanism in regulation of myocardial regeneration and functional recovery after BMSC transplantation.