中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (10): 1755-1764.doi: 10.4103/1673-5374.257531

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

可溶性Nogo受体1融合蛋白可增强神经祖细胞对脑卒中的神经保护作用

  

  • 出版日期:2019-10-15 发布日期:2019-10-15
  • 基金资助:

    国家自然科学基金(81671882，81471832)；广东省自然科学基金会(2016A030311039)；中国广东省科学和技术基金会(20150920212012，2017A020224012)；中国广州市科学技术基金会(201707010373)

Soluble Nogo receptor 1 fusion protein protects neural progenitor cells in rats with ischemic stroke

Hai-Wei He 1, 2, Yue-Lin Zhang 2, Bao-Qi Yu 3, Gen Ye 2, Wei You 2, Kwok-fai So 4, Xin Li 1, 2,   

  1. 1 School of Medicine, South China University of Technology, Guangzhou, Guangdong Province, China
    2 Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong  Academy of Medical Sciences, Guangzhou, Guangdong Province, China
    3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Key Laboratory of Remodelling- related Cardiovascular Diseases, Ministry of Education, Beijing, China
    4 School of Biomedical Sciences, The State Key Laboratory of Brain and Cognitive sciences, Li Ka Shing Faculty of Medicine, The University of
    Hong Kong, Hong Kong Special Administrative Region, China
  • Online:2019-10-15 Published:2019-10-15
  • Contact: Xin Li, MD, PhD, xlidoct@qq.com
  • Supported by:

    This study was supported by the National Natural Science Foundation of China, No. 81671882, 81471832 (to XL); the Natural Science Foundation of Guangdong Province of China, No. 2016A030311039 (to XL); the Science and Technology Foundation of Guangdong Province of China, No. 2015A020212012, 2017A020224012 (to XL); the Science and Technology Foundation of Guangzhou City of China, No. 201707010373 (to XL).

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摘要：

可溶性Nogo66受体-融合蛋白(sNgR-Fc)参与中枢神经系统损伤后的轴突再生，然而其潜在的机制仍不明确。为探讨sNgR-Fc对神经祖细胞的神经再生影响，实验从SD大鼠胚胎海马中分离出外源性神经祖细胞，采用光化学法建立SD大鼠顶叶皮质光凝血缺血模型，建模后随机分为sNgR-Fc组和光凝血缺血模型组，分别接受400 μg/kg的sNgR-Fc和同体积PBS输注于侧脑室，连续3 d。用BrdU染色法观察了sNgR-Fc对内源性神经祖细胞增殖和分化的影响，用水迷宫实验评价各组大鼠的神经行为学变化。为进一步研究sNgR-Fc治疗对神经祖细胞的影响，在另一批大鼠中也诱导光凝血缺血模型并进行NPCs(来源于SD大鼠胚胎海马)移植，随后大鼠接受PBS(神经祖细胞组)或sNgR-Fc输注(sNgR-Fc+神经祖细胞)于侧脑室，连续3 d。结果显示：(1)与体外对照组或者体内光凝血缺血模型组相比较，sNgR-Fc不仅能促进体外培养的神经祖细胞和光凝血缺血模型大鼠内源性神经祖细胞的增殖，还能诱导神经祖细胞向神经元的分化；(2)与光凝血缺血模型组相比较，sNgR-Fc治疗大鼠神经功能明显改善，表现在水迷宫实验逃避潜伏期明显减少，目标象限上爬得更远以及神经严重程度评分降低；(3)与神经祖细胞组比较，sNgR-Fc输注可显著改善移植神经祖细胞的存活和分化；(4)上述数据表明，sNgR-Fc在神经祖细胞的增殖、迁移和分化中起着重要的调节作用。sNgR-Fc具有治疗脑卒中和神经退行性疾病的开发潜力。

orcid: 0000-0003-0469-5121 (Xin Li)

 

关键词: Nogo-66受体, Nogo-66受体-Fc蛋白, 神经祖细胞, 增殖, 分化, 脑卒中, 光凝血缺血, 移植, 神经功能, 神经再生

Abstract:

Soluble Nogo66 receptor-Fc protein (sNgR-Fc) enhances axonal regeneration following central nervous system injury. However, the underlying mechanisms remain unclear. In this study, we investigated the effects of sNgR-Fc on the proliferation and differentiation of neural progenitor cells. The photothrombotic cortical injury model of ischemic stroke was produced in the parietal cortex of Sprague-Dawley rats. The rats with photothrombotic cortical injury were randomized to receive infusion of 400 μg/kg sNgR-Fc (sNgR-Fc group) or an equal volume of phosphate-buffered saline (photothrombotic cortical injury group) into the lateral ventricle for 3 days. The effects of sNgR-Fc on the proliferation and differentiation of endogenous neural progenitor cells were examined using BrdU staining. Neurological function was evaluated with the Morris water maze test. To further examine the effects of sNgR-Fc treatment on neural progenitor cells, photothrombotic cortical injury was produced in another group of rats that received transplantation of neural progenitor cells from the hippocampus of embryonic Sprague-Dawley rats. The animals were then given an infusion of phosphate-buffered saline (neural progenitor cells group) or sNgR-Fc (sNgR-Fc + neural progenitor cells group) into the lateral ventricle for 3 days. sNgR-Fc enhanced the proliferation of cultured neural progenitor cells in vitro as well as that of endogenous neural progenitor cells in vivo, compared with phosphate-buffered saline, and it also induced the differentiation of neural progenitor cells into neurons. Compared with the photothrombotic cortical injury group, escape latency in the Morris water maze and neurological severity score were greatly reduced, and distance traveled in the target quadrant was considerably increased in the sNgR-Fc group, indicating a substantial improvement in neurological function. Furthermore, compared with phosphate-buffered saline infusion, sNgR-Fc infusion strikingly improved the survival and differentiation of grafted neural progenitor cells. Our findings show that sNgR-Fc regulates neural progenitor cell proliferation, migration and differentiation. Therefore, sNgR-Fc is a potential novel therapy for stroke and neurodegenerative diseases, The protocols were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong (approval No. 4560-17) in November, 2015.

Key words: neural regeneration, Nogo-66 receptor, Nogo66 receptor-Fc protein, neural progenitor cells, proliferation, differentiation, stroke, photothrombotic cortical injury, transplantation, neurological function, nerve regeneration