miR-17-92基因簇调控神经干（前体）细胞移植后分化的机制研究

Neural Stem/progenitor cells (NSPCs) transplantation is a promising strategy for neurodegenerative diseases and brain injury. However, the low yield of NSPC-derived neurons hampers their potential for neuronal replacement. Circumstantial evidence suggests that neuroinflammation is usually aroused during the process of diseases or injury, even after cell replacement. The inflammation environment causes the activation of endogenous glia cells that release cytokines such as LIF or CNTF, which further facilitate astrogenesis, thus reducing the neuronal differentiation from NSPCs. Our study indicates that miR-17-92 cluster, which has multiple targets related to the signaling pathway of those cytokines, may block the effect of these molecules on cells. Therefore, we proposed that cytokines produced during neuroinflammation affect the differentiation of NSPCs, causing the low yield of NSPCs derived neurons. Overexpression of miR-17-92 can block the effect of cytokines on the differentiation of NSPCs, which increases the ratio of neuronal differentiation and improves brain lesions after cell transplantation. This project not only helps us to elucidate the mechanism underlying the neuroinflammation affected NSPCs differentiation but also provides us with new venues for cell replacement therapy for neurodegenerative diseases and brain injury.

在神经干（前体）细胞（NSPCs）移植治疗神经系统损伤或疾病的研究中，NSPCs分化形成神经元的比例较低，影响了移植后的治疗效果。研究显示，神经系统损伤或疾病，以及细胞移植均会引起神经炎症反应，激活内源性胶质细胞，释放细胞因子如LIF，CNTF等。上述因子信号通路的激活会促进NSPCs向星形胶质细胞分化，减少神经元的比例。我们的研究提示miR-17-92基因簇能抑制LIF，CNTF等因子信号通路中多个关键蛋白，阻断相关信号通路的激活。由此我们假设，神经炎症环境下产生的细胞因子影响了NSPCs移植后的分化命运，导致神经元分化数量不足；用miR-17-92早期干预NSPCs，可以阻断细胞因子对NSPCs分化的影响，提高神经元的分化比例，改善细胞移植的治疗效果。该研究有助于我们阐明神经炎症环境影响NSPCs分化的分子机制并寻找有效的干预手段，为细胞移植治疗神经系统损伤和疾病的研究提供了新的思路。

在移植神经前体细胞治疗神经系统损伤或疾病的过程中，由于神经炎症的微环境影响，移植后的神经前体细胞（NSPCs）分化成神经元的比例很低，降低了细胞移植后的治疗效果。本项目研究神经炎症环境影响神经前体细胞分化的分子机制和信号通路，利用miRNA靶向信号通路中的关键分子，从而调控细胞分化命运，提高神经元的分化产率。我们发现炎症环境中分泌的LIF和CNTF等因子，激活了神经前体细胞中的JAK2-STAT3信号通路，阻碍了神经前体细胞向神经元方向分化；而过表达miR-17-92可以同时抑制信号通路中的多个关键蛋白，阻断LIF和CNTF等因子的下游信号，从而提高神经元的分化比例，改善细胞移植后的治疗效果。上述干预手段的有效性在离体和在体水平上均得到了证明。本项目研究阐明了神经炎症环境影响神经前体细胞分化的分子机制，并找到了基于miR-17-92基因簇的有效干预手段，提高了细胞移植后神经元的分化比例，为细胞移植治疗神经系统损伤的研究开拓了新的方向。