中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 1124-1134.doi: 10.4103/1673-5374.355818

• 原著:视神经损伤修复保护与再生 • 上一篇    下一篇

过表达NeuroD1可将Müller细胞重新编程为多种类型的视网膜神经元

  


  • 出版日期:2023-05-15 发布日期:2022-10-26
  • 基金资助:
    广东省脑疾病治疗重大技术项目(2018B030332001);广州市脑科学和类脑智能技术重点项目(2020073009);广东省基础与应用基础研究基金项目(2020A1515110898)

Overexpressing NeuroD1 reprograms Müller cells into various types of retinal neurons

Di Xu1, Li-Ting Zhong1, Hai-Yang Cheng1, Zeng-Qiang Wang1, Xiong-Min Chen1, Ai-Ying Feng1, Wei-Yi Chen1, Gong Chen1, *, Ying Xu1, 2, *   

  1. 1Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, Guangzhou, Guangdong Province, China;  2Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
  • Online:2023-05-15 Published:2022-10-26
  • Contact: Ying Xu, PhD, xuying@jnu.edu.cn; Gong Chen, PhD, gongchen@jnu.edu.cn.
  • Supported by:
    This study was supported by the Guangdong Grant Key Technologies for Treatment of Brain Disorders, China, No. 2018B030332001 (to GC); the Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology, No. 20200730009 (to YX); and the Guangdong Basic and Applied Basic Research Foundation, No. 2020A1515110898 (to WYC). 

摘要:

视网膜退行性疾病的发病常与神经元缺失有关,因而,如何再生新的神经元以恢复视力已成为一个重要问题。NeuroD1是一种神经转录因子,能够在体内将脑星形胶质细胞重编程为神经元。此次实验证明了NeuroD1可将视网膜中的主要神经胶质细胞Müller细胞重编程为成年小鼠的视网膜神经元。最引人注目的是,相同转录因子NeuroD1以2种不同病毒载体的异位表达可将Müller胞转分化为不同的细胞。具体来说,AAV7m8 GFAP681::GFP-ND1可将Müller细胞转分化为视网膜内核层神经元,包括无长突细胞和一些神经节细胞。而AAV9 GFAP104::ND1-GFP则可将Müller细胞转分化为视网膜外核层神经元,即感光细胞和少数水平细胞,且具有更高的转换效率。此外研究还证明了由AAV9 GFAP104::ND1-GFP诱导的Müller细胞的转分化表现出明显的剂量依赖性和时间依赖性。上述结果表明,成年小鼠的Müller细胞具有高度可塑性,可重新编程为多种视网膜的神经元亚型。

https://orcid.org/0000-0002-7840-9047 (Di Xu); 

https://orcid.org/0000-0002-1857-3670 (Gong Chen); 

https://orcid.org/0000-0002-9987-2057 (Ying Xu)

关键词: NeuroD1, Müller细胞, 体内重编程, 视网膜, 感光器, 水平细胞, 无长突细胞, 神经节细胞, 视网膜变性, 再生

Abstract: The onset of retinal degenerative disease is often associated with neuronal loss. Therefore, how to regenerate new neurons to restore vision is an important issue. NeuroD1 is a neural transcription factor with the ability to reprogram brain astrocytes into neurons in vivo. Here, we demonstrate that in adult mice, NeuroD1 can reprogram Müller cells, the principal glial cell type in the retina, to become retinal neurons. Most strikingly, ectopic expression of NeuroD1 using two different viral vectors converted Müller cells into different cell types. Specifically, AAV7m8 GFAP681::GFP-ND1 converted Müller cells into inner retinal neurons, including amacrine cells and ganglion cells. In contrast, AAV9 GFAP104::ND1-GFP converted Müller cells into outer retinal neurons such as photoreceptors and horizontal cells, with higher conversion efficiency. Furthermore, we demonstrate that Müller cell conversion induced by AAV9 GFAP104::ND1-GFP displayed clear dose- and time-dependence. These results indicate that Müller cells in adult mice are highly plastic and can be reprogrammed into various subtypes of retinal neurons. 

Key words: amacrine cell, ganglion cell, horizontal cell, in vivo reprogramming, Müller cell, NeuroD1, photoreceptor, regeneration, retina, retinal degeneration