抑制LINGO-1促进移植人少突胶质前体细胞分化和髓鞘化的实验研究

新生儿脑白质损伤（white matter injury，WMI）是儿童脑瘫和智障的主要原因之一，无特效疗法。少突胶质前体细胞(oligodendrocyte progenitor cells,OPCs)是中枢神经系统的成髓鞘细胞，有望治疗此疾病。但将人OPCs移植到脑白质损伤模型大鼠脑后分化髓鞘化困难，我们在新生鼠脑白质损伤模型中发现LINGO-1高表达，现已证明LINGO-1是抑制动物OPCs分化和髓鞘化的关键因素，推测其可能与此有关。申请者在国内率先获得人神经干细胞诱导的OPCs，拟分别通过RNAi降低LINGO-1表达及拮抗其蛋白功能后，观察人OPCs在体外和移植到WMI大鼠模型后的分化和髓鞘形成情况，分析LINGO-1功能，并进一步研究相关的信号通路。探索LINGO-1在人OPCs分化、髓鞘化中的功能及调控机制将为未来OPCs移植治疗新生儿WMI提供理论依据与技术支持。

White matter injury (WMI), for which no effective therapy has been foud yet, is one of the main causes for children with cerebral palsy or mental retardation. Oligodendrocyte progenitor cells (OPCs) are the precursor cells of myelin-forming cells in the central nervous system, and OPCs transplantation brings hope for WMI. However, the poor differentiation and myelination of transplanted human OPCs in WMI rats inhibit the application of OPCs. We found the expression of LINGO-1 increasing in the injured area of WMI rats. In addition, several studies showed that LINGO-1 played crucial and inhibitory role in differentiation and myelination of OPCs of animal origin. Therefore we speculate that the upregulation of LINGO-1 may be the key factor that inhibit the transplanted OPCs differentiation and myelination. The applicant takes the lead in gaining human OPCs from neural stem cells, and will carry out a new research to down-regulate the mRNA expression of LINGO-1 by siRNA or block the LINGO-1 fuction by special antibody respectively, and then observe the OPCs differentiation and myelination in vitro and in WMI rats, analyze the function of LINGO-1 in the differentiation and myelination of transplanted OPCs and further research associated signaling pathways. This study will provide new ideas and technical support for drug development or the treatment of newborn with WMI by OPCs transplantation.