OBJECTIVES The goal of this study was to investigate the effect of growth factors on cardiomyogenic differentiation and cytoprotective effect of mesenchymal stem cells (MSCs), and their therapeutic efficacy after myocardial infarction.
BACKGROUND MSCs have potential to repair damaged myocardium. However, the underlying mechanisms have not been fully elucidated and therapeutic efficacy needs to be enhanced.
METHODS MSCs obtained from the bone marrow of Fisher344 rats were treated with fibroblast growth factor 2, insulin-like growth factor 1, and bone morphogenetic protein 2. The expression of cardiac specific markers and cytoprotective effect of MSCs were evaluated. In vivo study, MSCs were injected into the border zone of rat myocardial infarction model.
RESULTS Growth factors enhanced expression of cardiac transcription factors, and connexin-43 in MSCs when co-cultured with cardiomyocytes. Compared with untreated MSCs, gap junctional communication with cardiomyocytes was more active in treated MSCs. In co-culture condition, treated MSCs showed prominent protective effects on cardiomyocytes exposed to hypoxia, which was markedly reduced by gap junction blocking. Implantation of pretreated MSCs decreased infarction size and showed better left ventricular systolic function than untreated MSCs. Gap junction formation was more frequent and apoptosis decreased in pretreated MSC group compared with untreated MSCs. Arrhythmogeneity was not increased by growth factor pretreatment.
CONCLUSIONS Pretreatment with growth factors of MSCs enhanced the expression of connexin-43 and gap junction mediated cytoprotective effects on cardiomyocytes, a novel mechanism to explain therapeutic effect of MSCs. Growth factors may have important implication to enhance therapeutic efficacy of MSCs for damaged myocardium.