牙周膜干细胞外泌体miR-92a-3p通过Mfn1/ROS/HIF1α/LDHA通路调节巨噬细胞代谢和破骨分化

间充质干细胞和巨噬细胞（Mø）的细胞间通讯对骨稳态起到关键作用。牙周炎的牙槽骨吸收是制约临床治疗的关键。在牙槽骨微环境中，牙周膜干细胞（PDLSCs）与Mø之间的信号交流及调控机制尚无详细报道。课题组首次发现，健康人牙周膜干细胞外泌体（H-PDLSCs-Exo）可抑制Mø线粒体融合、氧化磷酸化和破骨分化，而牙周炎来源PDLSCs-Exo的抑制作用明显减弱；外泌体中差异表达的miR-92a-3p可抑制线粒体融合基因Mfn1表达。因此我们推测，H-PDLSCs-Exo可通过miR-92a-3p调节Mø线粒体动力学和代谢重编程，从而抑制破骨分化。本项目拟通过CRISPR/Cas9基因敲除技术、非靶向代谢组学分析和构建牙周炎动物模型等手段，阐明H-PDLSCs-Exo中miR-92a-3p通过调控Mø的线粒体动力学、代谢学，从而抑制破骨分化的机制，为临床治疗牙周炎提供新的思路，并开发新的治疗靶点。

The intercellular communication between mesenchymal stem cells and macrophages (Mø) plays a vital role in maintaining bone homeostasis. In periodontitis, the mechanism of alveolar bone resorption is unknown, which is the key to the clinical treatment. In the alveolar bone microenvironment, the signal communication between periodontal ligament stem cells (PDLSCs) and Mø has not been reported in detail. Our studies found that healthy human periodontal membrane stem cell exosomes (H-PDLSCs-Exo) could inhibit Mø’s mitochondrial fusion, oxidative phosphorylation and osteoclast differentiation, while the inhibitory effect of exosomes from periodontitis was weakened. Differential expression of exosomal miR-92a-3p inhibited the expression of Mfn1. Therefore, we speculate that H-PDLSCs-Exo regulates Mø’s mitochondrial dynamics and metabolism through mir-92a-3p, thereby inhibiting osteoclast differentiation and maintaining bone homeostasis. By means of CRISPR/Cas9 gene knockout technology, untargeted metabolomics analysis and the construction of periodontitis animals, this project intends to elucidate the mechanism that mir-92a-3p in H-PDLSCs-Exo inhibits osteoclast differentiation by regulating the mitochondrial dynamics and metabolism of Mø, so as to provide new ideas for clinical treatment of periodontitis and develop new therapeutic targets.