Transplantation of hypoxia-inducible factor-1α gene modified neural stem cells increases cell survival and angiogenesis after cerebral ischemia

Abstract

Previous studies have indicated the beneficial effects of transplanted neural stem cells (NSCs) on cerebral ischemia. Hypoxia-inducible factor-1α (HIF-1α) is a master transcription factor of cellular hypoxic gene expression, and its signal pathway might be the primary mechanism through which hypoxia promotes the growth of NSCs. To test the hypothesis that HIF-1α contributes to the therapeutic effect of NSCs transplantation in cerebral ischemia, we compared the efficacy of transplanting PBS, NSCs infected with recombinant adenovirus, HIF-1α gene and NSCs infected with a recombinant adenovirus vector with HIF-1α gene (HIF-1α-NSCs). A transient middle cerebral artery occlusion (tMCAO) was used in this study. PBS, HIF-1α gene, NSCs and HIF-1α-NSCs were respectively injected into cortical peri-infarction of the rat brain at 24 h after MCAO. Neurological deficits were assessed using the modified neurological severity score (NSS). Immunohistochemistry for BrdU, VEGF, Von Willebrand Factor and Nissl staining were performed. Compared with other groups HIF-1α-NSCs showed better behavioral recovery at 7, 14, 21and 28 days, and lesser degree of brain atrophy in cortex and hemisphere. More BrdU-positive cells in HIF-1α-NSCs group than that in NSCs group. Expression of VEGF and Von Willebrand Factor are both higher in HIF-1α-NSCs than those in HIF-1α or in NSCs group. Thus, we concluded that during the early period after transplantation HIF-1α infected NSCs expressed gene products，which reduce brain injury by improving the survival of NSCs and protecting the vascular system．