Transplantation of human neural stem cells protect against ischemia in a preventive mode via hypoxia-inducible factor-1α stabilization in the host brain

Hypoxia-inducible factor-1 (HIF-1) plays important roles in the prevention of cerebral ischemia. Deferoxamine (DFX), an iron chelator stabilizes the HIF-1α and activates target genes involved in compensation for ischemia. In this study, we are to investigate whether HIF-1α can be stabilized in human neural stem cells (NSCs) by DFX, and pre-transplantation of NSCs with HIF-1α stabilization can induce prolonged ischemic tolerance. In the DFX-treated NSCs, the HIF-1α protein expression was increased about 100-fold time-dependently, and subsequent transcriptional activation (VEGF, BDNF and CXCR4) was also observed. To test an ability to induce ischemic prevention in vivo, DFX-treated NSCs or naïve NSCs were transplanted in the striatum of adult rats. Seven days following the transplantation, focal cerebral ischemia was done. Infarct volumes were reduced in both NSCs-transplanted groups, compared with ischemia-only, but more reduced in DFX-treated NSCs group. The protective effects of NSCs were ablated when HIF-1α was silenced. HIF-1α protein levels were increased in both NSCs-transplanted groups, but more increased in DFX-treated NSCs group. RT-PCR analysis manifested a downregulation of mRNA expression of TNF-α, IL-6 and MMP-9 in both NSCs groups, but further decrease in DFX-treated NSCs group. These findings provide evidence that HIF-1α stabilization in human NSCs can be achieved effectively by DFX, and HIF-1α-stabilized NSCs protect against ischemia in a preventive mode.