Phosphatidylinositol-3-kinase-gamma is integral to homing functions of progenitor cells.
Endothelial progenitor cells (EPCs) and hematopoietic progenitor cells are recruited to ischemic regions, improving neovascularization. beta1 and beta2 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 gamma (PI3Kgamma) is the PI3K isoform that selectively transduces signals from G protein-coupled receptors. Here, we investigated the role of PI3Kgamma as a signaling intermediate in the chemokine-induced integrin-dependent homing functions of progenitor cells. A pharmacological PI3Kgamma inhibitor significantly reduced chemokine-induced chemotaxis and stromal cell-derived factor (SDF)1alpha-induced transmigration of human EPCs. Moreover, the PI3Kgamma inhibitor significantly reduced SDF1alpha-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 PI3Kgamma-deficient mice that displayed reduced SDF1alpha-induced migration and intercellular adhesion molecule-1 adhesion as compared with wild-type cells. Pharmacological inhibition or genetic ablation of PI3Kgamma reduced SDF1alpha-induced integrin activation in human EPCs and in murine Lin(-) BM-derived progenitor cells, respectively. In vivo, the homing of PI3Kgamma-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, PI3Kgamma is integral to the integrin-dependent homing of progenitor cells.
Chavakis
Emmanouil
E
Molecular Cardiology, Department of Internal Medicine III, J. W. Goethe University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. Chavakis@em.uni-frankfurt.de
Carmona
Guillaume
G
Urbich
Carmen
C
Göttig
Stephan
S
Henschler
Reinhard
R
Penninger
Josef M
JM
Zeiher
Andreas M
AM
Chavakis
Triantafyllos
T
Dimmeler
Stefanie
S
D000818:Animals; D002417:Cattle; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology*; D002633:Chemotaxis; D058544:Class Ib Phosphatidylinositol 3-Kinase; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007511:Ischemia / Q000473:pathology*; D007527:Isoenzymes / Q000172:deficiency / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D014471:Umbilical Veins / Q000166:cytology
D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D016023:Integrins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse