缺氧诱导因子-1α在脑缺血后对内源性神经干细胞作用的研究进展

摘要/Abstract

摘要：

目前脑缺血后促进内源性神经干细胞（neural stem cells，NSCs）再生的影响因素已成为神经病学研究的热点。近年来，有实验证明一些相关因子在脑梗死后缺血缺氧条件下被高度表达并参与了脑组织损伤的修复过程，如缺氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）。许多研究利用大鼠脑缺血模型进行免疫组化和蛋白印迹分析来评估内源性NSCs与HIF-1α早期表达的关系，结果表明在缺血造成的内环境中，HIF-1α的早期表达能够使内源性NSCs促进神经细胞的再生。而且脑梗死后，HIF-1α在缺血缺氧的环境中高度表达并发挥神经保护作用，为脑损伤的修复提供了有利的基础条件。

文章导读： 内源性神经干细胞治疗卒中被寄予厚望，但其对脑组织的修复作用非常有限。缺氧诱导因子-1α如何激活内源性神经干细胞，促进其在局部增殖、迁移和分化是目前迫切研究的方向之一。

关键词: 神经干细胞; 神经前体细胞; 缺氧诱导因子-1α 血管内皮生长因子; 促红细胞生成素; 一氧化氮合酶; 内环境

Abstract:

Influence factors of promoting the regeneration of endogenous neural stem cells (NSCs) after cerebral infarction are becoming a hot spot of concern for neurological scholars. In recent years, some experiments have been proven that some related factors involved in the brain tissue damage repair process and got highly expressed in the condition of ischemia and hypoxia after cerebral infarction, such as hypoxia-inducible factor-1α (HIF-1α). Experts evaluated the relationships between endogenous NSCs and HIF-1α expression in a photothromobotic rat stroke model using immunohistochemistry and Western blot analysis. The results showed that early expressions of HIF-1α after ischemia made up the microenvironment to increase the nerve regeneration for endogenous NSCs. A large number of studies have shown that high expressions of HIF-1α protect nerve cells from damage after cerebral ischemia in ischemic and anoxic environment and provide the favorable conditions for brain repair.

Key words: Neural stem cell; Neural precursor cell; Hypoxia-inducible factor 1α; Vascular endothelial growth factor; Erythropoietin; Nitric oxide synthase; Microenvironment

李栋，段淑荣. 缺氧诱导因子-1α在脑缺血后对内源性神经干细胞作用的研究进展 [J]. 中国卒中杂志, 2015, 10(07): 612-615.

WU Hao, GAO Wen-Chao, XU Sheng-Yuan, et al.. HIF-1α Playing a Role of Endogenous Neural Stem Cells after Cerebral Ischemia and Its Research Progress[J]. Chinese Journal of Stroke, 2015, 10(07): 612-615.

参考文献

参考文献

1 Ibrayeva A, Bonaguidi MA. Pushing and pulling on adult neural stem cells[J]. Cell Stem Cell, 2015, 16:451-452.

2 Duan SR, Wang JX, Teng WL, et al. Expression of nestin and glial-derived neurotrophic factor in human endogenous neural stem cells following ischemia[J]. Neurolo Res, 2010, 32:835-840.

3 段淑荣, 王慧慧, 戚基萍, 等. 脑缺血后碱性成纤维细胞生长因子、表皮生长因子对内源性神经干细胞增殖的影响[J]. 中华医学杂志, 2008, 47:3337-3341.

4 徐冉, 段淑荣, 王慧慧, 等. 人脑梗死后转化生长因子-β及血管内皮生长因子的表达及意义[J]. 中国全科医学, 2010, 13:2560-2563.

5 Lin R, Iacovitti L. Classic and novel stem cell niches in brain homeostasis and repair[J]. Brain Res, 2015, 28:8986-8993.

6 Jin K, Minami M, Lan JQ, et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat[J]. Proc Natl Acad Sci USA, 2001, 98:4710-4715.

7 Parent JM, Vexler ZS, Gong C, et al. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke[J]. Ann Neurol, 2002, 52:802-813.

8 Thored P, Arvidsson A, Cacci E, et al. Persistent production of neurons from adult brain stem cells during recovery after stroke[J]. Stem Cells, 2006, 24:739-747.

9 Zhao J, Han J, Jiang J, et al. The downregulation of Wnt/β-catenin signaling pathway is associated with zinc deficiency-induced proliferative deficit of C17.2 neural stem cells[J]. Brain Res, 2015, 4:324-328.

10 Wang Q, Yang L, Wang L. Enhanced differentiation of neural stem cells to neurons and promotion of neurite outgrowth by oxygen-glucose deprivation[J]. Int J Dev Neurosci, 2015, 4:50-57.

11 Ingram N, Porter CD. Transcriptional targeting of acute hypoxia in the tumour stroma is a novel and viable strategy for cancer gene therapy[J]. Gene Ther, 2005, 12:1058-1069.

12 Matsuda T, Abe T, Wu JL, et al. Hypoxia-inducible factor-1 alpha DNA induced angiogenesis in a rat cerebral ischemia model[J]. Neurol Res, 2005, 27:503-508.

13 Anan M, Abe T, Matsuda T, et al. Induced angiogenesis under cerebral ischemia by cyclooxygenase 2 and hypoxia-inducible factor naked DNA in a rat indirect-bypass model[J]. Neurosci Lett, 2006, 409:118-123.

14 Turcotte S, Desrosiers RR, Beliveau R. HIF-1 alpha mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma[J]. Cell Sci, 2003, 116:2247-2260.

15 Bemaudin M, Nedelec AS, Divoux D, et al. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia inducible factor 1 and its target genes, erythropoietin and VEGF, in the adult mouse brain[J]. J Cereb Blood Flow Metab, 2002, 22:393-403.

16 Hamrick SE, McQuillen PS, Jiang X, et al. A role for hypoxia inducible factor 1 alpha in desferoxamine neuroprotection[J]. Neurosci Lett, 2005, 379:96-100.

17 Para AL, Rodriguez JC. Nasal neuro EPO could be a reliable choice for neuroprotective stroke treatment[J]. Cent Nerv Syst Agents Med Chem, 2012, 12:60-68.

18 Bath PM, Sprigg N, England T. Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke[J]. Cochrane Database Syst Rev, 2013, 24:52-57.

19 赵舒武, 高英茂, 张晓丽, 等. EPO对体外培养的神经干细胞增殖、分化和凋亡的影响[J]. 神经解剖学杂志, 2007, 23:549-553.

20 Park MH, Lee SM, Lee JW, et al. ERK-mediated production of neurotrophic factors by astrocytes promotes neuronal stem cell differentiation of erythropoietin[J]. Biochem Biophys Res Commun, 2006, 339:1021-1028.

21 Dooley D, Vidal P, Hendrix S. Immunopharmacological intervention for successful neural stem cell therapy:New perspectives in CNS neurogenesis and repair[J]. Pharmacol Ther, 2014, 141:21-31.

22 Chen C, Wang Y, Goh SS, et al. Inhibition of neuronal nitric oxide synthase activity promotes migration of human-induced pluripotent stem cell-derived neural stem cells towards cancer cells[J]. J Neurochem, 2013, 126:318-330.

23 Pena-Altamira E, Petazzi P, Contestable A. Nitrc oxide control of proliferation in nerve cells and in tumor cells of nervous origin[J]. Curr Pharm Des, 2010, 16:440-450.

24 Zhang H, Hayashi T, Tsuru K, et al. Vascular endothelial growth factor promotes brain tissue regeneration with a novel biomaterial polydimethylsiloxane-tetraethoxysilane[J]. Brain Res, 2007, 1132:29-35.

25 Schmidt NO, Koeder D, Messing M, et al. Vascular endothelial growth factor-stimulated cerebral microvascular endothelial cells mediate the recruitment of neural stem cells to the neurovascular niche[J]. Brain Res, 2009, 126:24-37.

26 Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia:role the HIF system[J]. Nat Med, 2003, 9:677-684.

27 Mazure NM, Brahimi-Horn MC, Pouyssegur J. Protein kinases and the hypoxia-inducible factor-1, two switches in angiogeneis[J]. Curr Pharm Des, 2003, 9:531-541.

28 Hirota K. Hypoxia-inducible factor 1, a master transcription factor of cellular hypoxia gene expression[J]. Anesth, 2002, 16:150-159.

29 Liu LX, Lu H, Luo Y, et al. Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1[J]. Biochem Biophys Res Commun, 2002, 291:908-914.

30 Kim BK, Kim SE, Shim JH, et al. Neurogenic effect of vascular endothelial growth factor during germ layer formation of human embryonic stem cells[J]. FEBS Lett, 2006, 580:5869-5874.

[1]	涂鄂文, 刘秋庭, 谭莉, 曾艳香, 陈琼. 丁基苯酞对脑出血大鼠血管内皮生长因子、血管生成素-2蛋白表达及血管新生的影响[J]. 中国卒中杂志, 2019, 14(12): 1225-1231.
[2]	白家赫，于永鹏，刘丽君，郑亚利，李鑫，谭兰. 脑微出血影像学分类与血浆血管内皮生长因子水平及载脂蛋白E基因分型的关系研究[J]. 中国卒中杂志, 2019, 14(09): 856-864.
[3]	姜辰, 杨浩鹏. 葛根素对小鼠脑缺血再灌注损伤的神经保护作用及机制研究[J]. 中国卒中杂志, 2018, 13(01): 58-63.
[4]	刘磊，王佳伟. 干扰长单一序列区83基因对人巨细胞病毒感染后人脑血管平滑肌促血管生成素及血管内皮生长因子表达的影响[J]. 中国卒中杂志, 2017, 12(09): 800-807.
[5]	林亚航，陈明，段淑荣. 缺氧诱导因子-1α对脑梗死后内源性神经干细胞作用的研究进展[J]. 中国卒中杂志, 2017, 12(01): 89-93.
[6]	杨炎歌，段淑荣. 脑梗死后VEGF及bFGF对神经干细胞增殖分化的机制研究进展[J]. 中国卒中杂志, 2016, 11(08): 704-708.
[7]	雷延成，吴世政，张淑坤，侯倩，才鼎，肖宗宇，陈晓娟. 缺氧预处理后骨髓源神经干细胞联合脑源性神经生长因子移植治疗大鼠脑缺血再灌注损伤的研究[J]. 中国卒中杂志, 2016, 11(05): 360-367.
[8]	高雁青1，张淑坤2，吴世政2. 急进高原的健康人群脑血管反应性研究[J]. 中国卒中杂志, 2013, 8(06): 449-453.
[9]	王彬，刘志辉，张培，李健. 酒精对缺血-再灌注大鼠脑组织的保护作用[J]. 中国卒中杂志, 2013, 8(04): 266-270.
[10]	张红霞1，邵蓓1，王柳清1，林真珍1，肖丽1，蒋慧刚1，程一帆1，苏巧尔1，郑伟明2，诸葛启钏2，. 大脑老化与神经再生和卒中[J]. 中国卒中杂志, 2013, 8(02): 147-152.
[11]	林真珍，王柳清，邵蓓. 缺血性卒中后血管新生的细胞和分子调节机制[J]. 卒中杂志, 2012, 7(12): 941-947.
[12]	王柳清，邵蓓，王虹. 血管新生与缺血性卒中的相关性研究进展[J]. 卒中杂志, 2012, 7(12): 948-952.
[13]	王国峰;刘伯芹;赵玉芳;赵仁亮. 缺血预处理对脑缺血大鼠血管内皮生长因子表达及微血管密度变化的影响[J]. , 2011, 6(11): 869-875.
[14]	董漪;董强. 血管内皮生长因子与卒中及神经系统退行性疾病[J]. , 2009, 4(02): 152-157.
[15]	于秋红;张红霞;刘亚玲;吴雅丽;吉康祥;薛连璧. 单次9小时高压氧超早期治疗对大鼠脑梗死体积的影响[J]. , 2008, 3(09): 662-666.