Phosphatidylinositol-3-kinase-γ is integral to homing functions of progenitor cells

被引：52

作者：

Chavakis, Emmanouil ^{[1
]}

Carmona, Guillaume ^{[1
]}

Urbich, Carmen ^{[1
]}

Goettig, Stephan ^{[2
]}

Henschler, Reinhard ^{[2
]}

Penninger, Josef M. ^{[3
]}

Zeiher, Andreas M. ^{[1
]}

Chavakis, Triantafyllos ^{[4
]}

Dimmeler, Stefanie ^{[1
]}

机构：

[1] Goethe Univ Frankfurt, Dept Internal Med 3, D-60590 Frankfurt, Germany

[2] Goethe Univ Frankfurt, DRK Inst Transfus Med & Immune Hematol, D-60590 Frankfurt, Germany

[3] Inst Mol Biotechnol, Vienna, Austria

[4] NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA

来源：

CIRCULATION RESEARCH | 2008年 / 102卷 / 08期

关键词：

progenitor cells; homing; integrins; adhesion; migration; PI3K gamma; neovascularization;

D O I：

10.1161/CIRCRESAHA.107.164376

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Endothelial progenitor cells (EPCs) and hematopoietic progenitor cells are recruited to ischemic regions, improving neovascularization. beta 1 and beta 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 phosphatidylinositol-3-kinase catalytic subunit gamma (PI3K gamma) is the PI3K isoform that selectively transduces signals from G protein-coupled receptors. Here, we investigated the role of PI3K gamma as a signaling intermediate in the chemokine-induced integrin-dependent homing functions of progenitor cells. A pharmacological PI3K gamma inhibitor significantly reduced chemokine-induced chemotaxis and stromal cell-derived factor (SDF)1 alpha-induced transmigration of human EPCs. Moreover, the PI3K gamma inhibitor significantly reduced SDF1 alpha-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 gamma-deficient mice that displayed reduced SDF1 alpha-induced migration and intercellular adhesion molecule-1 adhesion as compared with wild-type cells. Pharmacological inhibition or genetic ablation of PI3K gamma reduced SDF1 alpha-induced integrin activation in human EPCs and in murine Lin(-) BM-derived progenitor cells, respectively. In vivo, the homing of PI3K gamma-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 gamma is integral to the integrin-dependent homing of progenitor cells.

引用

页码：942 / 949

页数：8

共 56 条

[1] Stromal cell-derived factor-1α plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury [J].