Smpd3介导OPC外泌体释放在激活M1型小胶质细胞和参与MS病程进展中的作用及机制研究

最新研究发现少突胶质前体细胞OPC除形成髓鞘外，还具有免疫调节功能。预实验显示Wnt高度激活的OPC具有激活M1型小胶质细胞的能力，可能是MS髓鞘损伤复发、进展和新损伤灶形成的重要环节。但MS中M1型小胶质细胞的激活机制不清。外泌体作为较特异性的OPC-小胶质细胞信号传递方式，可被Wnt下游分子Smpd3调控，而外泌体中的microRNA等物质具有激活M1型小胶质细胞的功能。因此我们推测：MS中，Wnt激活的OPC通过增强Smpd3表达，促进OPC—小胶质细胞间的外泌体传递，激活M1型小胶质细胞，是病程进展和新损伤灶形成的重要环节。本研究将明确OPC对M1型小胶质细胞激活和病程进展的作用；证明Wnt调控下的Smpd3介导了外泌体释放和M1型小胶质细胞激活；探讨OPC外泌体中的重要成分。我们的研究结果将有助于揭示MS病程进展的细胞和分子机制，为阻断复发、进展和治疗提供新的实验证据和研究靶点。

Recent research has found that besides myelination, oligodendrocyte progenitor cells (OPCs) also has immunoregulation capabilities. Previous results by our lab demonstrate that Wnt signaling pathway highly activated OPC can activate M1 microglia cells, suggesting OPC-derived microglia polarization may be essential for MS myelin injury recurrence、relapse and new lesion formation. Polarization of M1 microglia cells play important roles in MS progression, but the regulatory mechanism is still unclear. As a specific OPC-microglia information transmission approach, exosome transmitting was found to be regulated by Wnt signaling pathway downstream molecule Smpd3, and microRNAs in exosome can be reposible for the polarization of M1 microglia. Therefore, we raised up our hypothesis as follows: in MS, Wnt activated OPC promote the expression of Smpd3, which promotes the exosome transmission between OPC and microglias. This process activates M1 microglia and is an essential process in pathological progression and new lesion formation. Our research aims to clarify the role of OPC in M1 microglia activation and pathological progression, proving that Wnt regulated Smpd3 induced exosome release and M1 microglia activation, and study important constituents in OPC exosome. Our study will help reveal cellular and molecular mechanism in MS progression, and provide new experiment evidence and research targets for preventing disease recurrence, progress and treatments.