工程化小胶质细胞外泌体促进卒中大鼠白质修复的作用机制研究

卒中后白质修复和神经功能恢复密切相关，但目前对损伤白质的治疗手段缺乏。我们前期发现静脉移植M2型小胶质细胞的外泌体可促进卒中大鼠白质部分修复，而且其富含miR-23a，可能在白质修复中起关键作用。但静脉移植外泌体在脑中存留少，对白质的修复有限，且治疗机制仍不明确。本课题拟通过微流控技术制备透明质酸微球作为外泌体的递送载体，并进一步修饰外泌体，从分子、细胞和整体水平探索：1）M2型小胶质细胞外泌体是否通过miR-23a作用于下游靶蛋白从而促进少突胶质前体细胞的功能和白质修复；2）原位移植负载外泌体的微球到脑损伤区能否增加其在脑中的存留促进白质修复；3）在外泌体表面修饰促少突胶质前体细胞迁移的CXCL12多肽并过表达miR-23a，负载于透明质酸微球并原位移植到损伤脑中，是否能促进少突胶质前体细胞对外泌体的摄取，从而进一步促进白质修复。本研究将为外泌体对卒中后白质修复提供理论依据和治疗策略。

White matter repair is closely related to the recovery of patients' neurological function after stroke. However，currently there is a lack of treatment for damaged white matter. Our previous study showed that intravenous injection of M2 microglia derived exosomes partially promoted white matter repair in rats after stroke, and M2 microglia derived exosomes were enriched with miR-23a, which may play a critical role in promoting white matter repair. However, the number of exosomes remained in the brain after intravenous injection is low, leading to limited white matter repair after stroke. In addition, the underlying mechanism of exosome-mediated white matter repair after stroke is still unclear. In this study, by developing hyaluronic acid microsphere as a delivery vehicle for exosome using microfluidic technology, and further modify the exosomes, we aim to explore: 1) Whether M2 microglia-derived exosomes promote the function of oligodendrocyte progenitor cell and white matter repair through miR-23a and its downstream target protein; 2) Whether transplantation of exosome-loaded hyaluronic acid microspheres into ischemic brain in situ can promote its retention in the brain and improve white matter repair after stroke; 3) Whether transplantation of hyaluronic acid microspheres loaded with M2 microglia derived exosomes that modified with oligodendrocyte progenitor cell migration peptide CXCL12 and over-expression of miR-23a could increase the uptake of exosomes into oligodendrocyte progenitor cells, further improve white matter repair after stroke. Our study will provide new theoretical basis and novel treatment strategy for M2 microglia derived exosomes to repair white matter after stroke.