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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Emmanouil Chavakis - , University Hospital Frankfurt, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Guillaume Carmona - (Author)
  • Carmen Urbich - (Author)
  • Stephan Göttig - (Author)
  • Reinhard Henschler - (Author)
  • Josef M. Penninger - (Author)
  • Andreas M. Zeiher - , University Hospital Frankfurt, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)
  • Triantafyllos Chavakis - , Institute of Clinical Chemistry and Laboratory Medicine, National Cancer Institute (NCI) (Author)
  • Stefanie Dimmeler - , University Hospital Frankfurt, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Author)

Abstract

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.

Details

Original languageEnglish
Pages (from-to)942-949
JournalCirculation Research
Volume102
Issue number8
Publication statusPublished - 25 Apr 2008
Peer-reviewedYes

External IDs

PubMed 18323525
Scopus 42549125520

Keywords

Library keywords