In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function.

It is hypothesized that the protection of bone marrow stem cells (BMSCs) on ischemic myocardium might be related to the anti-apoptotic effect via paracrine mechanisms. In this study, a wide array of cytokines including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), stromal cell-derived factor-1 (SDF-1) and insulin growth factor-1 (IGF-1) were detected in the BMSCs cultured medium by ELISA. Myocyte apoptosis was assayed by DNA fragmentation and annexin-V staining. Myocardial infarction model was produced by ligation of mouse left anterior descending coronary artery (LAD). Before LAD ligation, mice were myoablated by irradiation and transplanted with bone marrow cells from transgenic mice expressing green fluorescent protein (GFP). After LAD ligation, animals were administered stem cell factor (SCF, 200 mug/day/kg, i.p.) or saline for 6 days. Animals were sacrificed at 4 weeks after SCF treatment. Apoptotic cardiomyocytes were analyzed by TUNEL. Myocardial function was analyzed by echocardiography and pressure-volume system. Bcl-2 protein was analyzed by Western blotting. Our results showed that cultured BMSCs released VEGF, bFGF, SDF-1 and IGF-1. Hypoxia-induced cell apoptosis was diminished in cardiomyocytes co-cultured with BMSCs. Smaller LV dimension and increased LV ejection fraction were seen in SCF-treated animals. SCF significantly reduced cardiomyocytes apoptosis within peri-infarct area and increased up-regulation expression of Bcl-2 in ischemic area. Moreover, conditioned medium from cultured BMSCs also induced up-regulation of Bcl-2 protein in cardiomyocytes. It is concluded that paracrine mediators secreted by BMSCs might be involved in early repair of ischemic heart by preventing cardiomyocytes apoptosis and improving cardiac function.