In vivo therapy of myocardial infarction with mesenchymal stem cells modified with prostaglandin I synthase gene improves cardiac performance in mice

Aim: Intra-myocardial injection of adult bone marrow-derived stem cells (MSC) has recently been proposed as a therapy to repair damaged cardiomyocytes after acute myocardial infarction (AMI). PGI(2) has vasodilatation effects; however, the effects of combining both MSC and PGI(2) therapy on AMI have never been evaluated. Main methods: We genetically enhanced prostaglandin I synthase (PGIS) gene expression in mouse mesenchymal stem cells (MSC) using lentiviral vector transduction (MSCPGIS). Mice were subjected to an AMI model and injected (intra-myocardially) with either 5 x 10(4) MSCs or MSCPGIS before surgery. Fourteen days post AMI, mice were analyzed with echocardiography, immunohistochemistry, and apoptotic, and traditional tissue assays. Key findings: Lenti-PGIS transduction did not change any characteristic of the MSCs. PGIS over-expressed MSCs secreted 6-keto-PGF1 alpha in the culture medium and decreased free radical damage during hypoxia/re-oxygenation and H2O2 treatment Furthermore, splenocyte proliferation was significantly suppressed with MSCPGIS as compared with MSCs alone. Fourteen days post AMI, echocardiography showed more improvement in cardiac function of the MSCPGIS group than the MSC alone group, sham-operated group, or artery ligation only group. The histology of MSCPGIS treated hearts revealed MSCs in the infarcted region and decreased myocardial fibrosis/apoptosis with limited cardiac remodeling. Furthermore, the level of the vascular endothelial growth factor was elevated in the MSCPGIS group as compared to the other three groups. Significance: In summary, our results provide both in vitro and in vivo evidence for the beneficial role of MSCPGIS in limiting the process of detrimental cardiac remodeling in a mouse AMI model during early stages of the disease. (C) 2011 Elsevier Inc. All rights reserved.