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

Abstract

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 (MSC(PGIS)). Mice were subjected to an AMI model and injected (intra-myocardially) with either 5×10(4) MSCs or MSC(PGIS) 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-PGF1α in the culture medium and decreased free radical damage during hypoxia/re-oxygenation and H(2)O(2) treatment. Furthermore, splenocyte proliferation was significantly suppressed with MSC(PGIS) as compared with MSCs alone. Fourteen days post AMI, echocardiography showed more improvement in cardiac function of the MSC(PGIS) group than the MSC alone group, sham-operated group, or artery ligation only group. The histology of MSC(PGIS) 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 MSC(PGIS) 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 MSC(PGIS) in limiting the process of detrimental cardiac remodeling in a mouse AMI model during early stages of the disease.