The efficacy of mesenchymal stem cell (MSC) therapy for myocardial regeneration is limited by the poor survival of stem cells after transplantation into the infarcted heart. To improve the cell survival of MSCs in the infarcted heart, MSCs were genetically engineered to overexpress phosphoinositide-3-kinase class II alpha (PI3K-C2 alpha). PI3K-C2 alpha overexpression increased PI3K expression and the cell viability of MSCs. Furthermore, levels of survival-related phosphorylation were elevated in PI3K-C2 alpha-MSC5. But, the level of apoptotic proteins downregulated and the number of PI-positive cells decreased in PI3K-C2a-MSC5 compared to hypoxic MSCs. Nine rats per group had 1 x 10(6) cells (20 mu I PBS) transplanted after myocardial infarction. One week after transplantation, infarct size and area of fibrosis were reduced in the PI3K-C2 alpha-MSC-transplanted group. The number of TUNEL positive cells declined, while the mean microvessel count per field was higher in the PI3K-C2 alpha-MSC group than the MSC-injected group. Heart function was improved in the PI3K-C2 alpha-MSC5 group as assessed using a Millar catheter at 3 weeks after transplantation. These findings suggest that overexpression of PI3K-C2a in MSCs can assist cell survival and enhance myocardial regeneration. (C) 2010 Elsevier Inc. All rights reserved.