Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia

Abstract

Although mesenchymal stem cells (MSCs) have therapeutic potential for tissue injury, intolerance and poor cell viability limit their reparative capability. Therefore, we examined the impact of bone marrow-derived MSCs, in which heme oxygenase-1 (HO-1) was transiently overexpressed, on the repair of an ischemic myocardial injury. When MSCs and HO-1-overexpressed MSCs (MSCHO-1) were exposed to serum deprivation/hypoxia or H2O2-induced oxidative stress, MSCHO-1 exhibited increased resistance to cell apoptosis compared with MSCs (17 ± 1 vs. 30 ± 2%, P < 0.05) and were markedly resistant to cell death (2 ± 1 vs. 32 ± 2%, P < 0.05). Under these conditions, vascular endothelial growth factor (VEGF) production was 2.1-fold greater in MSCHO-1 than in MSCs. Pretreatment of MSCs and MSCHO-1 with phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt) pathway inhibitors such as LY-294002 (50 μM) or wortmannin (100 nM) significantly decreased VEGF production. In a rat infarction model with MSCs or MSCHO-1 (5 × 106 ± 0.1 × 106 cells/rat) transplantation, the number of TdT-mediated dUTP nick end-labeling-positive cells was significantly lower in the MSCHO-1 group than in the MSC group (12.1 ± 1.0 cells/field vs. 26.5 ± 2.6, P < 0.05) on the 4th day after cell transplantation. On the 28th day, increased capillary density associated with decreased infarction size was observed in the MSCHO-1 group (1,415 ± 47/mm2 with 21.6 ± 2.3%) compared with those in the MSCs group (1,215 ± 43/mm2 with 28.2 ± 2.3%, P < 0.05), although infarction size relative to area at risk was not different in each group at 24 h after transplantation. These results demonstrate that MSCHO-1 exhibit markedly enhanced anti-apoptotic and anti-oxidative capabilities compared with MSCs, thus contributing to improved repair of ischemic myocardial injury through cell survival and VEGF production associated with the PI 3-kinase/Akt pathway.