Department of Renal Transplant, Center of Nephropathy, The First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, 710061 Shaanxi, China.
Biochem Biophys Res Commun. 2010 Oct 29;401(4):509-15. doi: 10.1016/j.bbrc.2010.09.076. Epub 2010 Sep 24.
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.
最近的证据表明，骨髓间充质干细胞（MSCs）在移植前进行亚致死性低氧预处理（HP）可以通过尚未明确的机制改善其在靶组织中存活和植入的能力。在这项研究中，我们证明 HP（3%氧气）诱导 MSCs 中趋化因子基质衍生因子-1（SDF-1）受体 CXCR4 和 CXCR7 的高表达。HP 还改善了 MSC 的体外迁移、黏附和存活。尽管 SDF-1 诱导的 HP-MSC 迁移仅被抗 CXCR4 抗体所阻断，但 CXCR4 和 CXCR7 均负责提高 HP-MSC 的黏附能力。此外，CXCR7 但不是 CXCR4 对于 HP-MSC 抵抗氧化应激是必需的。此外，HP 还引起缺氧诱导因子-1（HIF-1α）表达增加和 Akt 的磷酸化。HIF-1α 的化学诱导剂去铁胺（DFX）和氯化钴（CoCl₂）在常氧条件下诱导 MSC 中 CXCR4 和 CXCR7 的表达上调。相反，siRNA 阻断 HIF-1α 和wortmannin 或 LY294002 抑制 Akt 均消除了 HP 诱导的 MSC 中 CXCR4 和 CXCR7 的上调。总之，这些发现为 PI3K/Akt-HIF-1α-CXCR4/CXCR7 通路在增强 HP-MSC 的体外迁移、黏附和存活中发挥关键作用提供了证据。
