VEGF overexpression improves mesenchymal stem cell sheet transplantation therapy for acute myocardial infarction

Abstract

Cell sheet-based tissue engineering shows great potential in the treatment of ischaemic heart disease. However, treatment efficacy is compromised by low blood and nutrient supply. The aim of this study was to investigate the effect of pro-angiogenic vascular endothelial growth factor (VEGF)-modified mesenchymal stem cell (MSC) sheet transplantation therapy in ischaemic heart failure. Rat MSCs were manipulated to overexpress the VEGF gene. In vitro, the antiapoptotic and paracrine effects were assessed under hypoxic conditions. In vivo, we evaluated the therapeutic effect of VEGF-modified MSC sheet therapy in a rat model of acute myocardial infarction (AMI). Forty-five Wistar rats were divided into three groups; one group underwent AMI (control), another underwent AMI and WT sheet transplantation (WT-MSC) and a third group underwent AMI and VEGF sheet transplantation (VEGF-MSC). Echocardiography was performed after 3, 10 and 28 days. Samples for histological analysis were collected at the end of the study. The VEGF gene protected MSCs against apoptosis. In vitro, VEGF overexpression significantly reduced MSC apoptosis compared with wild-type and enhanced VEGF secretion under hypoxic conditions. Capillary density in the infarct border zone was higher in VEGF-MSC-transplanted animals than in WT-MSC-treated animals. Furthermore, VEGF-MSC-transplanted animals had a smaller infarct size than WT-MSC-treated animals and exhibited remarkable functional recovery. These findings support the premise that transplantation of proangiogenic gene-modified MSCs may be valuable for mediating substantial functional recovery after AMI. Copyright © 2012 John Wiley & Sons, Ltd.