Survival enhancement of mesenchymal stem cells by phosphoinositide 3-kinase after transplantation into the infarcted myocardium
Dept. of Medicine/박사
Mesenchymal stem cell (MSC) therapy for myocardial regeneration has a limitation due to the poor survival of stem cell after cell transplantation in infarcted heart. Members of the phosphoinositide 3-kinase (PI3K) family regulate fundamental cellular responses, including proliferation, growth, chemotaxis, and survival. To improve the cell survival in the infarcted heart, MSCs were genetically engineered to overexpress class II PI3K α (PI3K-C2α). Expression of endogenous PI3K-C2α was time-dependently decreased in hypoxic condition. PI3K-C2α overexpression exerted an increase of endogenous PI3K-C2α expression and of cell viability in MSCs. The survival signaling, including phosphorylation of Akt, Bad, cAMP-response element-binding protein (CREB) and IκB kinase (IKK) respectively augmented in PI3K-C2α-MSCs. The Bcl-2/Bax ratio of PI3K-C2α-MSCs also had a great increase under hypoxic condition for 12 hr. However, the cleavage of poly (ADP-ribose) polymerase (PARP) expression and PI positive cells were decreased in PI3K-C2α-MSCs compared to hypoxic MSCs. The adhesion of MSCs was strengthened by overexpressing of PI3K-C2α on cardiogel (3D-matrix). Nine rats per group were transplanted with 1x106 cells (20 μl PBS) after myocardial infarction. One week after transplantation, reduced infarct size and fibrosis area were observed in PI3K-C2α-MSCs-transplanted group. According to morphologic analysis, TUNEL positive cells and neutrophils were also declined, but the mean microvessel count per field was higher in PI3K-C2α-MSCs group compared to MSCs-injected group. These findings suggest that overexpression of PI3K-C2α in MSCs can assist cell survival and enhance myocardial regeneration.