Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
J Clin Neurosci. 2010 Jan;17(1):92-5. doi: 10.1016/j.jocn.2009.03.039. Epub 2009 Nov 12.
We explored the possibility that hypoxia-inducible factor-1alpha (HIF-1alpha) might contribute to the therapeutic effect of neural stem cell (NSC) transplantation in cerebral ischemia. The relative efficacy of modified NSC to promote behavioral recovery was investigated in a rat model of stroke induced by a transient middle cerebral artery occlusion (MCAO). A recombinant adenovirus (Ad-HIF-1alpha) was engineered to express HIF-1alpha. Control NSC infected with control adenovirus (NSC-Ad), recombinant adenovirus Ad-HIF-1alpha, or NSC infected by Ad-HIF-1alpha (NSC-Ad-HIF-1alpha), were used for intraventricular transplantion into rat brain 24 hours after MCAO. Neurological deficits were assessed over 4 weeks using the modified neurological severity scale (NSS) score. Long-term in vivo expression of HIF-1alpha was demonstrated by Western blotting and immunocytochemistry, and derivatives of nestin-positive transplanted cells contributed to both neuronal (neurofilament-positive) and astroglial (glial fibrillary acidic protein-positive) lineages. All animals showed functional improvement. Improvement was accelerated in animals receiving either NSC-Ad or Ad-HIF-1alpha, while improvement at all times between 7 days and 28 days post MCAO was significantly greater in animals transplanted with NSC-Ad-HIF-1alpha than for other treated animals. NSC-Ad-HIF-1alpha cells also increased the number of factor VIII-positive cells in the region of ischemic injury, indicating that HIF-1alpha expression can promote angiogenesis. Gene-modified NSC expressing HIF-1alpha have therapeutic potential in ischemic stroke.
我们探讨了缺氧诱导因子-1alpha（HIF-1alpha）可能有助于神经干细胞（NSC）移植治疗脑缺血的可能性。通过短暂性大脑中动脉闭塞（MCAO）诱导的大鼠中风模型，研究了改良 NSC 促进行为恢复的相对疗效。构建了一种表达 HIF-1alpha 的重组腺病毒（Ad-HIF-1alpha）。用感染对照腺病毒（NSC-Ad）、重组腺病毒 Ad-HIF-1alpha 或 Ad-HIF-1alpha 感染的 NSC（NSC-Ad-HIF-1alpha）的 NSC 进行脑室移植，在 MCAO 后 24 小时进行。用改良神经功能缺损评分（NSS）评分在 4 周内评估神经功能缺损。通过 Western blot 和免疫细胞化学证实 HIF-1alpha 的长期体内表达，巢蛋白阳性移植细胞的衍生物有助于神经元（神经丝阳性）和星形胶质细胞（胶质纤维酸性蛋白阳性）谱系。所有动物均表现出功能改善。接受 NSC-Ad 或 Ad-HIF-1alpha 治疗的动物改善速度加快，而在 MCAO 后 7 天至 28 天之间的所有时间，接受 NSC-Ad-HIF-1alpha 移植的动物的改善程度均显著大于其他治疗动物。NSC-Ad-HIF-1alpha 细胞还增加了缺血损伤区域的因子 VIII 阳性细胞的数量，表明 HIF-1alpha 表达可以促进血管生成。表达 HIF-1alpha 的基因修饰 NSC 在缺血性中风中具有治疗潜力。
