rTMS诱导外泌体中miR-188-3p调控间充质干细胞（MSCs）迁移归巢至脑梗死边缘区的作用机制

近期报道重复经颅磁刺激（rTMS）联合间充质干细胞（MSCs）治疗可明显改善脑损伤大鼠的神经功能，但其分子机制尚不明确。我们预实验发现rTMS可募集MSCs迁移归巢至脑梗死边缘区，诱导神经前体细胞增殖及抑制炎性微环境而改善其神经功能。机制研究显示：①rTMS可促进脑部外泌体分泌增多；②经高通量RNA测序显示miR-188-3p在外泌体中显著高表达；③miR-188-3p可下调血管内皮细胞Claudin5蛋白和激活Wnt/β-catenin信号通路及上调CXCL12表达。因此我们提出假设：rTMS通过诱导外泌体中miR-188-3p下调Claudin5及激活Wnt/β-catenin/CXCL12信号轴而募集MSCs迁移归巢至脑梗死边缘区，进而改善脑梗死大鼠神经功能。本研究拟构建MCAO大鼠模型并结合体外细胞实验详细阐明rTMS诱导MSCs迁移归巢的分子机制，为脑卒中治疗提供新的治疗思路。

It has been recently reported that repetitive transcranial magnetic stimulation (rTMS) combined with mesenchymal stem cells (MSCs) therapy can significantly improve the neurological functions in brain injury rats, but the mechanism remains unclear. Our preliminary experiments showed that rTMS could recruit MSCs homing to the ischemic penumbra region, induce the proliferation of neural precursor cells and modify inflammatory microenvironment to improve the neurological function of rats with cerebral infarction. The mechanism study showed that: ① Exosomes increased significantly in brain after rTMS treatment. ② The high-throughput RNA sequencing analysis indicated that miR-188-3p was highly expressed in rTMS-induced exosomes.③ miR-188-3p could significantly down-regulate endothelial cell adhesion protein Claudin 5, activate Wnt/beta-catenin signaling pathway and up-regulate CXCL12 expression. Therefore, we hypothesized that miRNA-188-3p in rTMS-induced exosomes could improve the neurological function of rats by down-regulating Claudin 5 and activating Wnt/beta-catenin/CXCL12 signal axis to recruit MSCs homing to the ischemic penumbra region. This study will elucidate the mechanism of rTMS induced mesenchymal stem cells (MSCs) homing to ischemic penumbra region by using the MCAO model and vitro cell experiments, and highlight a new therapeutic idea for stroke.