Phosphatidylinositol-3-Kinase- Is Integral to Homing Functions of Progenitor Cells

Endothelial progenitor cells (EPCs) and hematopoietic progenitor cells are recruited to ischemic regions, improving neovascularization. 1 and 2 integrins play a crucial role for progenitor cell homing to ischemic tissues. Integrin activity is regulated by chemokines and their respective G protein–coupled receptors. The phosphatidylinositol3-kinase catalytic subunit (PI3K ) is the PI3K isoform that selectively transduces signals from G protein–coupled receptors. Here, we investigated the role of PI3K as a signaling intermediate in the chemokine-induced integrindependent homing functions of progenitor cells. A pharmacological PI3K inhibitor significantly reduced chemokineinduced chemotaxis and stromal cell–derived factor (SDF)1 -induced transmigration of human EPCs. Moreover, the PI3K inhibitor significantly reduced SDF1 -induced adhesion of EPCs to intercellular adhesion molecule-1 and human umbilical vein endothelial cell monolayers. These findings were corroborated with Lin bone marrow–derived progenitor cells from PI3K -deficient mice that displayed reduced SDF1 -induced migration and intercellular adhesion molecule-1 adhesion as compared with wild-type cells. Pharmacological inhibition or genetic ablation of PI3K reduced SDF1 -induced integrin activation in human EPCs and in murine Lin BM-derived progenitor cells, respectively. In vivo, the homing of PI3K -deficient Lin progenitor cells to ischemic muscles after intravenous infusion in the model of hindlimb ischemia and their neovascularization-promoting capacity was reduced as compared with wild-type cells. In conclusion, PI3K is integral to the integrin-dependent homing of progenitor cells. (Circ Res. 2008;102:942-949.)