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-1α) and phosphorylation of Akt. The chemical inducers of HIF-1α, desferrioxamine (DFX) and cobalt chloride (CoCl2), induced upregulation of CXCR4 and CXCR7 expression in MSCs under normoxic conditions. Contrarily, blockade of HIF-1α 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-1α-CXCR4/CXCR7 pathway on enhanced migration, adhesion and survival of HP-MSCs in vitro.

Research highlights
► In vitro hypoxic preconditioning (HP) of mesenchymal stem cells (MSCs) upregulates the mRNA and protein expression of CXCR4 and CXCR7.
► CXCR4 and CXCR7 play an essential, but differential, role in regulating the migration, adhesion and survival of MSCs in vitro.
► The hypoxia-inducible factor-1 (HIF-1α) is activated by HP and promotes upregulation of CXCR4 and CXCR7 in MSCs.
► PI3K/Akt signaling pathway blockade inhibits HIF-1α activation and also abrogates HP-induced expression of CXCR4 and CXCR7 in MSCs.
► The PI3K/Akt-HIF-1α-CXCR4/CXCR7 pathway plays a crucial role on HP-enhanced migration, adhesion and survival of MSCs in vitro.