Abstract 14957: Implantation of Mesenchymal Stem Cells Overexpressing Pi3k Improves Cardiac Regeneration in the Infarcted Rat Heart
Emerging evidence suggests that cell therapy with bone marrow-derived mesenchymal stem cells (MSCs) can have favorable therapeutics for injured heart. However, decreased survival rate of MSCs in ischemic condition limits cell transplantation. Although to date the role of the class IA phosphoinositide 3-kinase (PI3K) is well reported in company with Akt, the physiological significance of α -isoform of class II PI3K (PI3K-C2α) is poorly understood in MSCs. This study aimed to investigate whether PI3K-C2α plays a determinant role of survival of MSCs and these cells can regenerate the infarcted myocardium. As a specific strategy to improve cell survival, MSCs were genetically engineered to overexpress PI3K-C2α with fused green fluorescent protein (GFP) by lentivirus system. PI3K expression was significantly decreased in hypoxic MSCs for 9 hr. The cell viability of hypoxic PI3K-C2α-transfected MSCs (PI3K-C2α-MSCs) was higher in comparison with MSCs and Mock-MSCs of hypoxic condition. These cells were promoted the survival signaling, phosphorylation of Akt, cAMP-response element-binding protein (CREB), and IκB kinase (IKK), ultimately. In addition, PI3K-C2α-MSCs regulated the phosphorylation of Bad. The cleavage of poly (ADP-ribose) polymerase (PARP), Bcl-2/Bax protein level, and PI ratio were contrastively declined in hypoxic PI3K-C2α-MSCs compared to MSCs. PI3K-C2α-MSCs were also strengthened in cardiogel (3D-matrix). Rats underwent transplantation of 1x 106 (20 μl PBS) MSCs, Mock-MSCs, or PI3K-C2α-MSCs after myocardial infarction via left anterior descending coronary artery ligation. PI3K-C2α-MSCs group exhibited a significant increase of green fluorescence compared with other groups. Infarct and fibrosis area of left ventricle were significantly decreased, and neutrophils and apoptotic cell death were also declined in PI3K-C2α-MSCs group. The mean microvessel count per field was higher in the infarcted heart of PI3K-C2α-MSCs group. These results suggest the PI3K-C2α gene transduction of MSCs regulates the increment of cell survival in hypoxic condition, and more effective than MSCs only after myocardial damage. The genetically engineered cells with PI3K-C2α may be critical for application of cell therapy in infarcted myocardium.
- © 2010 by American Heart Association, Inc.