中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (1): 130-136.doi: 10.4103/1673-5374.314316

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

细胞周期退出和神经分化蛋白1工程化的胚胎神经干细胞可促进脑损伤后神经元分化和神经功能恢复

  

  • 出版日期:2022-01-05 发布日期:2021-09-18

Cell cycle exit and neuronal differentiation 1-engineered embryonic neural stem cells enhance neuronal differentiation and neurobehavioral recovery after experimental traumatic brain injury

Ren Wang1, #, Dian-Xu Yang1, #, Ying-Liang Liu2, Jun Ding1, Yan Guo1, Wan-Hai Ding1, *, Heng-Li Tian1, *, Fang Yuan1, *   

  1. 1Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 2Department of Neurosurgery, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
  • Online:2022-01-05 Published:2021-09-18
  • Contact: Wan-Hai Ding, MD, PhD, dingwanhai@126.com; Heng-Li Tian, MD, PhD, tianhlsh@126.com; Fang Yuan, MD, PhD, yf021025@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81701895; and Shanghai Jiao Tong University Medicine-Engineering Research Fund, China, No. YG2016QN20 (both to FY).

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摘要：

研究显示细胞周期退出和神经分化蛋白1可能参与神经干细胞周期退出和定向分化，因而利用基因工程转染细胞周期退出和神经分化蛋白1的神经干细胞可能会更好地改善创伤性脑损伤的预后？（1）实验首先通过定量蛋白质组学分析发现创伤性脑损伤后，小鼠脑组织中细胞周期退出和神经分化蛋白1表达下调；（2）在创伤性脑损伤3d后，于小鼠损伤灶周围移植转染细胞周期退出和神经分化蛋白1的神经干细胞，结果显示，创伤性脑损伤5周时，移植转染细胞周期退出和神经分化蛋白1的神经干细胞的小鼠脑萎缩明显减轻，同时神经功能显著改善；（3）体内外实验结果均显示，细胞周期退出和神经分化蛋白1过表达可抑制神经干细胞的增殖，同时促进其神经元的分化。此外，细胞周期退出和神经分化蛋白1过表达还能下调神经干细胞中Notch1和cyclin D1的表达，但上调p21的表达。同时转染细胞周期退出和神经分化蛋白1的神经干细胞的治疗效果优于未转染神经干细胞；（4）表明细胞周期退出和神经分化蛋白1工程化的神经干细胞移植是一种潜在的治疗创伤性脑损伤疗法。实验于2016年11月25日经上海交通大学生物医学工程学院伦理委员会批准（批准号2016034）。

https://orcid.org/0000-0001-7772-8233 (Ren Wang); https://orcid.org/0000-0002-4060-7830 (Fang Yuan)

关键词: 细胞周期退出和神经分化蛋白1, 基因工程, 过表达, 胚胎神经干细胞, 神经元分化, Notch1, 细胞周期蛋白D1, p21, 大鼠, 创伤性脑损伤

Abstract: Our previous study showed that cell cycle exit and neuronal differentiation 1 (CEND1) may participate in neural stem cell cycle exit and oriented differentiation. However, whether CEND1-transfected neural stem cells can improve the prognosis of traumatic brain injury remained unclear. In this study, we performed quantitative proteomic analysis and found that after traumatic brain injury, CEND1 expression was downregulated in mouse brain tissue. Three days after traumatic brain injury, we transplanted CEND1-transfected neural stem cells into the area surrounding the injury site. We found that at 5 weeks after traumatic brain injury, transplantation of CEND1-transfected neural stem cells markedly alleviated brain atrophy and greatly improved neurological function. In vivo and in vitro results indicate that CEND1 overexpression inhibited the proliferation of neural stem cells, but significantly promoted their neuronal differentiation. Additionally, CEND1 overexpression reduced protein levels of Notch1 and cyclin D1, but increased levels of p21 in CEND1-transfected neural stem cells. Treatment with CEND1-transfected neural stem cells was superior to similar treatment without CEND1 transfection. These findings suggest that transplantation of CEND1-transfected neural stem cells is a promising cell therapy for traumatic brain injury. This study was approved by the Animal Ethics Committee of the School of Biomedical Engineering of Shanghai Jiao Tong University, China (approval No. 2016034) on November 25, 2016. 

Key words: cell cycle exit and neuronal differentiation 1, cyclin D1, embryonic neural stem cells, neuronal differentiation, genetic engineering, overexpression, mice, Notch1, p21, traumatic brain injury