HIF-1? promotes NSCs migration by modulating Slit2-Robo1 signaling after cerebral ischemia

Abstract

Our previous studies have shown that transplantation of Hypoxia-inducible factor-1? (HIF-1?) gene modified neural stem cells (NSCs) reduced brain injury by improving the survival of NSCs and protecting the vascular system. HIF-1? plays pivotal roles during hypoxia, and its downstream pathways might be the primary mechanisms for the growth of NSCs. However, there are very few studies reported whether HIF-1? regulates NSCs migration. In this study, to test the hypothesis that HIF-1? modulates migration of NSCs after cerebral ischemia, we compared the injection of HIF-1? gene recombinant adenovirus, and control adenovirus in ischemia penumbra at 24 h after transient middle cerebral artery occlusion (tMCAO). BrdU labeled NSCs were transplanted in the lateral ventricle at the same time in both groups. The modified neurological severity score (NSS) was used to evaluate neurological deficits. Immunohistochemistry for HIF-1?, BrdU, Slit2 and Robo1 were performed. Comparing with vehicle group HIF-1? group showed better behavioral recovery on day 21 and 28. Expression of HIF-1? in HIF-1? group is higher than that in vehicle group. In HIF-1? group, more BrdU-positive cells were found than that in vehicle group. There are increased Slit2 in HIF-1? group. However, robo1, a receptor of Slits is decreased than that in vehicle group. Thus, we concluded that in cerebral ischemia rat model HIF-1? increased NSCs migration by inhibiting Slit2-Robo1 pathway, and improved the neurological behavior. In conclusion, our results indicate that HIF-1? may be a potential therapeutic target for ischemic stroke through promoting neuroregeneration.