中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (2): 342-351.doi: 10.4103/1673-5374.265185

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

NeuroD1诱导星形胶质细胞在脑灰质与白质中神经元重编程的差异

  

  • 出版日期:2020-02-15 发布日期:2020-05-25
  • 基金资助:
    国家自然科学基金（31701291），中国博士后科学基金（2016M602600）和暨南大学内部资金（21616110）

Differential neuronal reprogramming induced by NeuroD1 from astrocytes in grey matter versus white matter

Min-Hui Liu1, Wen Li1, Jia-Jun Zheng1, Yu-Ge Xu1, Qing He1, Gong Chen1, 2   

  1. 1 Guangdong-HongKong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou, Guangdong Province, China
    2 Department of Biology, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA, USA
  • Online:2020-02-15 Published:2020-05-25
  • Contact: Wen Li, PhD, liwenhlb@163.com; Gong Chen, PhD,2755884965@qq.com.
  • Supported by:
    This work is supported in part by the National Natural Science Foundation of China (Grant No. 31701291 to WL, U1801681 to GC), the China Postdoctoral Science Foundation (Grant No. 2016M602600 to WL); the Guangdong Grant ‘Key Technologies for Treatment of Brain Disorders’ (Grant No. 2018B030332001 to GC) and the Internal Funding of Jinan University, China (Grant No. 21616110 to GC).

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摘要：

近年来，一种称为体内神经胶质细胞向神经元转化的新技术已成为神经再生和修复的新希望疗法，其通过在神经胶质细胞中异位表达神经转录因子，从而实现将内源神经胶质细胞重编程为神经元。以前的研究一直关注脑灰质中的神经胶质细胞，但脑白质中的神经胶质细胞是否可以重新编程尚未可知。为此，实验研究了成年小鼠脑灰质（大脑皮质和纹状体）和脑白质（胼胝体）中NeuroD1诱导的星形胶质细胞体内神经元重编程，了解星形胶质细胞向功能性神经元的转化效率，以及转化神经元亚型和电生理特征。结果发现NeuroD1可以有效地将脑灰质中的星形胶质细胞重编程为功能性神经元，但这一过程在脑白质中则进行得不顺利。来自大脑皮质和纹状体的星形胶质细胞能够转化神经元包括谷氨酸能和γ-氨基丁酸能神经元，并能够激发动作电位，又具有自发的突触活动。相比之下，脑白质中少数星形胶质细胞转化的神经元相当不成熟，突触活动少。这些结果证实了星形胶质细胞重编程为神经元的能力在脑灰质和脑白质中存在差异，体现了微环境对胶质细胞向神经元转化结果的影响。实验方案于2018年3月21日由暨南大学实验动物伦理委员会（批准号IACUC-20180321-03）批准。

orcid: 0000-0002-4632-5754 (Wen Li) 

         0000-0002-1857-3670 (Gong Chen)

关键词: 星形胶质细胞, 转换效率, 胼胝体, 皮质, 灰质, 体内细胞转化, NEUROD1, 神经元, 重新编程, 纹状体, 白质

Abstract: A new technology called in vivo glia-to-neuron conversion has emerged in recent years as a promising next generation therapy for neural regeneration and repair. This is achieved through reprogramming endogenous glial cells into neurons in the central nervous system through ectopically expressing neural transcriptional factors in glial cells. Previous studies have been focusing on glial cells in the grey matter such as the cortex and striatum, but whether glial cells in the white matter can be reprogrammed or not is unknown. To address this fundamental question, we express NeuroD1 in the astrocytes of both grey matter (cortex and striatum) and white matter (corpus callosum) to investigate the conversion efficiency, neuronal subtypes, and electrophysiological features of the converted neurons. We discover that NeuroD1 can efficiently reprogram the astrocytes in the grey matter into functional neurons, but the astrocytes in the white matter are much resistant to neuronal reprogramming. The converted neurons from cortical and striatal astrocytes are composed of both glutamatergic and GABAergic neurons, capable of firing action potentials and having spontaneous synaptic activities. In contrast, the few astrocyte-converted neurons in the white matter are rather immature with rare synaptic events. These results provide novel insights into the differential reprogramming capability between the astrocytes in the grey matter versus the white matter, and highlight the impact of regional astrocytes as well as microenvironment on the outcome of glia-toneuron conversion. Since human brain has large volume of white matter, this study will provide important guidance for future development of in vivo glia-to-neuron conversion technology into potential clinical therapies. Experimental protocols in this study were approved by the Laboratory Animal Ethics Committee of Jinan University (approval No. IACUC-20180321-03) on March 21, 2018.

Key words: astrocyte, conversion efficiency, corpus callosum, cortex, grey matter, in vivo cell conversion, NeuroD1, neuron, reprogramming, striatum, white matter