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.
Liu
Hongbao
H
Department of Renal Transplant, Center of Nephropathy, The First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, 710061 Shaanxi, China.
Xue
Wujun
W
Ge
Guanqun
G
Luo
Xiaohui
X
Li
Yang
Y
Xiang
Heli
H
Ding
Xiaoming
X
Tian
Puxun
P
Tian
Xiaohui
X
D000818:Animals; D002448:Cell Adhesion; D015687:Cell Hypoxia; D002465:Cell Movement; D002470:Cell Survival; D002478:Cells, Cultured; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054387:Receptors, CXCR / Q000096:biosynthesis*; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D015854:Up-Regulation
C501897:Cmkor1 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen