Gli1+间充质干细胞-H型血管耦联效应在牙周炎治疗中的作用和机制研究

牙周组织的功能重建是牙周炎治疗的难点，基于间充质干细胞（MSCs）的牙周组织再生是主要方向之一。Gli1+ MSCs是维持牙和骨等硬组织稳态的关键干细胞群。H型血管是介导骨形成与血管生成发生耦联关系的重要载体。申请人前期发现牙周膜中的Gli1+细胞集中分布于H型血管周，牙周炎时Gli1+细胞和H型血管同时减少，提示Gli1+ MSCs与H型血管可能存在重要的耦联效应，发挥调控牙周组织修复的作用。本研究拟①明确牙周组织Gli1+ MSCs-H型血管耦联效应：利用组织透明化技术从三维视角分析两者共定位关系；建立Gli1+细胞消融小鼠模型，观测H型血管生成变化；通过中和抗体抑制H型血管生成，分析对Gli1+细胞功能影响；②探究Hedgehog信号对该耦联效应的调控作用；③研究Hedgehog信号激动剂SAG通过增强该耦联效应促进牙周炎组织修复的潜能。研究结果将为基于干细胞的牙周炎治疗提供新思路。

Functional reconstruction of periodontal tissue is difficult in periodontitis treatment, while mesenchymal stem cells (MSCs)-based periodontal tissue regeneration is one of the major research directions. Gli1+ MSCs are key stem cell populations that maintain the homeostasis of hard tissues such as teeth and bone. Type H vessels are important mediators that couple angiogenesis and osteogenesis. Our preliminary studies revealed that Gli1+ cells were mainly distributed around the type H vessels in periodontal ligament. Gli1+ cells and type H vessels were simultaneously reduced upon periodontitis, suggesting their vital coupling effect in regulating periodontal tissue repair. The aims of this study include ① to clarify the coupling of Gli1+ MSCs and type H vessels in periodontium: analyzing the co-localization of Gli1+ cells and type H vessels from a three-dimensional perspective using tissue clearing technique; establishing a Gli1+ cell-ablated mouse model and detecting changes in type H vessels formation; using neutralizing antibody to inhibit type H vessels formation and then analyzing the impact on Gli1+ cells; ② to explore the regulatory role of Hedgehog signaling on this coupling effect; ③ to study the potential of SAG, an agonist of Hedgehog signaling, to enhance this coupling effect, and thus promoting periodontal tissue repair. Our results will offer new strategies for the stem cell-based treatment of periodontitis.