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(Circulation Research. 2008;102:942.)
© 2008 American Heart Association, Inc.

Cellular Biology

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

Emmanouil Chavakis, Guillaume Carmona, Carmen Urbich, Stephan Göttig, Reinhard Henschler, Josef M. Penninger, Andreas M. Zeiher, Triantafyllos Chavakis, Stefanie Dimmeler

From Molecular Cardiology, Department of Internal Medicine III (E.C., G.C., C.U., A.M.Z., S.D.), and the DRK Institute of Transfusion Medicine and Immune Hematology (S.G., R.H.), J. W. Goethe University Frankfurt, Germany; the Institute for Molecular Biotechnology (J.M.P.), Vienna, Austria; and the Experimental Immunology Branch (T.C.), National Cancer Institute, NIH, Bethesda, Md.

Correspondence to Emmanouil Chavakis, MD, Molecular Cardiology, Department of Internal Medicine III, J. W. Goethe University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Chavakis{at}em.uni-frankfurt.de

Endothelial progenitor cells (EPCs) and hematopoietic progenitor cells are recruited to ischemic regions, improving neovascularization. β1 and β2 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 phosphatidylinositol-3-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 integrin-dependent homing functions of progenitor cells. A pharmacological PI3K inhibitor significantly reduced chemokine-induced 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.

Key Words: progenitor cells • homing • integrins • adhesion • migration • PI3K • neovascularization

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