Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs

Recent evidence indicated that sublethal hypoxic preconditioning (HP) of bone marrow-derived mesenchymal stem cells (MSCs) before transplantation could ameliorate their capacity to survive and engraft in the target tissue through yet undefined mechanisms In this study we demonstrated that HP (3% oxygen) induced the high expression of both chemokine stromal-derived factor 1 (SDF-1) receptors CXCR4 and CXCR7 in MSCs HP also Improved in vitro migration adhesion and survival of MSCs Although SDF-1-induced migration of HP-MSCs was only abolished by an anti-CXCR4 antibody both CXCR4 and CXCR7 were responsible for elevated adhesion of HP-MSCs Moreover CXCR7 but not CXCR4 was essential for the resistance to oxidative stress of HP-MSC In addition HP also evoked an increase in expression of hypoxia-inducible factor-1 (HIF 1 alpha) and phosphorylation of Akt The chemical inducers of HIF-1 alpha desferrioxamine (DFX) and cobalt chloride (CoCl2) induced upregulation of CXCR4 and CXCR7 expression in MSCs under normoxic conditions Contrarily blockade of HIF-1 alpha by siRNA and inhibition of Akt by either wortmannin or LY294002 abrogated upregulation of HP-Induced CXCR4 and CXCR7 in MSCs Collectively these findings provide evidence for a crucial role of PI3K/Akt-HIF-1 alpha-CXCR4/CXCR7 pathway on enhanced migration adhesion and survival of HP-MSCs in vitro (C) 2010 Elsevier Inc All rights reserved