小胶质细胞清除髓鞘碎片的机制及在卒中后白质修复中的作用

缺血性卒中相关的脑白质损伤导致痴呆和神经功能缺损。我们发现缺血性卒中后小胶质细胞聚集在损伤髓鞘的周围，并存在吞噬死亡细胞和髓鞘碎片的现象，而在卒中后小胶质细胞介导的吞噬与髓鞘再生的关系，以及是否影响卒中预后，目前尚不清楚。本研究通过：1）流式细胞仪分选卒中急性期和恢复期的小胶质细胞进行转录组芯片测序，找出卒中后特有的具有吞噬功能和促进髓鞘再生功能分子的动态变化，结合卒中后白质损伤的病理结构，鉴定具有吞噬髓鞘作用的小胶质细胞新亚群；2）基于我们测序的结果，我们发现卒中后吞噬受体Axl的表达明显改变，生长阻滞特异性蛋白Gas6为Axl受体最重要的配体，Gas6/Axl信号介导的吞噬在卒中白质损伤中的功能未见报道。我们推测Gas6/Axl在吞噬髓鞘的小胶质细胞亚群中至关重要。通过本项目的研究，拟阐明小胶质细胞调控髓鞘碎片清除的机制在卒中后白质修复中的作用，为临床白质修复的治疗提供理论依据。

White matter injury secondary to ischemic stroke elicits memory impairments and neurological deficits. Our preliminary study demonstrated that activated microglia surrounded the damaged myelin and engulfed myelin debris after ischemic stroke. However, whether myelin clearance mediated by microglia promoted re-myelination and stroke recovery was unknown. In this project, 1) we extracted microglia from stroke model in acute stage and recovery stage by FACS. We are going to depict dynamic alternations of molecules relative to re-myelination and phagocytosis in ischemic stroke by RNA sequencing with the purpose to find out myelin-phagocytic microglia subgroup. 2) With the guide of our RNA-sequencing result, we observed profoundly enhancement of Axl expression on the microglia surface. Growth arrest specific protein 6 (Gas6) is the most important ligand of Axl. It remains to be elucidated the protective functions of Gas6/Axl in white matter injury after stroke. Whether microglia swallows apoptotic cells and myelin debris dependent on Gas6/Axl axis is unknown either. To fill these voids, our project is going to confirm Myelin debris clearance mediated by microglia promotes re-myelination after stroke and its underlying mechanisms. Our results provide a solid ground for devising means to restore myelination through modulating microglia phagocytosis in stroke.