不同脑区异质性对胶质细胞原位转分化的影响和机制研究

Neurological disorders in central nervous system (CNS) are difficult to cure, mainly due to the limited neuronal regeneration in the adulthood. Our team has pioneered an innovative technology, using a single proneural transcription factor NeuroD1 to efficiently convert cortical reactive glial cells into functional neurons in situ in brain trauma and Alzheimer's disease animal models, and the newly converted neurons can form new neural circuits. This study opens up a new field to treat neurological disorders with endogenous glial cells. But how to regenerate specific subtypes of neurons in different CNS regions is unknown. It has been hypothesized that both regional heterogeneity in glial cells from different CNS regions and different reprogramming transcription factors may participate in determining the neuronal subtypes. Following this hypothesis, applicant has recently ectopically expressed NeuroD1 in both cortical and striatal astrocytes and found that NeuroD1 can also convert striatal astrocytes into neurons. Thus, this project will further study whether and how the regional heterogeneity in astrocytes from cortex and striatum, as well as different proneural transcription factors (NeuroD1 and Ascl1) affect the efficiency of the neuronal reprogramming and the consequent neuronal subtypes. The completion of this project will enrich our knowledge on mechanisms behind the neuronal reprogramming and neuronal subtype determination, and provide the possibility using astrocytes in different CNS regions to regenerate proper subtypes of neurons to treat different types of neurological disorders.

中枢神经系统疾病的治疗是世界难题，主要原因是由于成年后绝大部分功能性神经元难以再生。本课题组前期研究发现转录因子NeuroD1可以在脑损伤动物模型中高效诱导皮层胶质细胞原位转分化为功能性神经元，并能形成新的神经环路，使通过转分化内源胶质细胞再生功能性神经元从而治疗中枢神经系统疾病成为可能。但是不同脑区胶质细胞的区域异质性及不同的转录因子均可能影响转分化效率及所得到的神经元的亚型，目前对此研究甚少。申请人近期研究发现NeuroD1也能将纹状体来源的星形胶质细胞转分化为神经元。本项目将进一步研究不同转录因子（NeuroD1和Ascl1）在体内及体外诱导不同来源（皮层及纹状体）星形胶质细胞转分化产生神经元的亚型及功能的差异，并进而探究其分子机制。本项目将拓展我们对胶质细胞转分化产生功能性神经元机制的理解，为利用胶质细胞原位转分化技术再生不同类型神经元、治疗多部位的中枢神经系统疾病提供理论依据。

大脑胶质细胞原位转分化技术利用大脑内源性的胶质细胞直接再生神经元，可以规避外源移植细胞的伦理问题和安全隐患，是治疗大脑疾病一条新思路。但是大脑内神经元种类繁多，如何在特定区域高效再生特定亚型的神经元是胶质细胞原位转分化技术应用于治疗神经系统疾病的亟待解决的问题之一。以往研究提示启动转分化的转录因子、胶质细胞的区域异质性以及内环境对转分化产生的神经元的效率和亚型具有影响，但是它们的影响程度和机制尚不明确。本研究同时利用体内和体外胶质细胞转分化系统，系统研究了神经转录因子NeuroD1和Ascl1诱导皮层和纹状体星形胶质细胞转分化产生神经元效率、转分化产生的神经元亚型以及功能的差异。研究结果显示神经转录因子对于诱导星形胶质细胞转分化产生神经元效率、神经元亚型和功能起决定性作用，但是星形胶质细胞区域特性以及微环境对神经元亚型和功能也存在影响，其中机制尚在进一步发掘之中。本研究结果可以拓展我们对胶质细胞转分化产生特定亚型神经元的理解，帮助我们寻找在大脑特定区域再生特定亚型神经元的更加有效的方法，为利用大脑胶质细胞原位转分化技术治疗神经系统疾病提供了理论基础。