线粒体生物合成在MSC促进MZB细胞分化治疗卒中相关性感染中的作用机制研究

卒中诱导的免疫抑制（SIDS）是引发卒中相关性感染（SAI）的主要原因。间质干细胞（MSC）能够维持免疫稳态，是治疗SAI理想选择，但其干预的靶细胞群及分子机制仍未阐明。申请人近期文章证实：MSC可保护固有样淋巴细胞MZB死亡减轻SIDS（STTT.2021）。预实验发现与MSC共培养后，MZB细胞向具有抗感染功能的IgM+浆细胞分化增加。线粒体是决定分化等细胞命运的关键细胞器，表达谱分析发现MSC显著上调MZB细胞中线粒体生物合成通路。据此我们提出假说：MSC通过增强MZB细胞线粒体生物合成，促进其分化为IgM+浆细胞进而治疗SAI。本课题拟利用转基因小鼠确证MZB细胞是介导MSC发挥抗感染功能的关键靶细胞群；通过RNA-seq、中和抗体等探索MSC上调MZB细胞线粒体生物合成促进其分化为IgM+浆细胞的分子机制。本项目将阐明MSC治疗SAI的细胞学及分子机制，为其临床应用提供理论支撑。

Stroke-induced immunodepression syndrome (SIDS) is the main cause of stroke-associated infections (SAI). With their potent immunomodulatory capacities, the mesenchymal stem cell (MSC) could be an ideal solution, but the underlying cellular and molecular mechanisms remain unknown. The applicant’s previous study has demonstrated that the administration of MSC alleviates SIDS by protecting the splenic marginal zone (MZ) B cells (Signal Transduct Target Ther. 2021). Furthermore, our preliminary experiments have found that co-culture with MSC promotes MZB cells differentiation into anti-infective IgM-expressing plasma cells. Emerging evidence suggests that mitochondria play an important role in cell fate determination such as cell differentiation. Furthermore, transcript profile analysis indicates mitochondrial biogenesis signalling is dramatically up-regulated in MZB cells after co-culture with MSCs. Based on these findings, we speculate that MSC could attenuate SAI by enhancing mitochondrial biosynthesis in MZB cells and promoting their differentiation into IgM+ plasma cells. This project aims to confirm that MZB cells are the main target cell subset of MSC therapy by using MZB cell-deficient CD19 knockout (KO) mouse model, and to explore the molecular mechanism of MSC promoting mitochondrial biogenesis-mediated MZB cells differentiation into IgM-secreting plasma cells through the application of RNA-seq and neutralizing antibodies etc. This study not only clarifies the cellular and molecular mechanisms of MSC therapy in treating SAI, but also provides necessary theoretical support for its clinical application.