基于单细胞测序研究Fat4+细胞亚群在正畸应力调控牙槽骨骨改建中的作用机制及谱系发生

应力介导的牙槽骨骨改建机制是正畸学科的核心科学问题。研究已证实BMSCs是调控骨改建的核心且对应力敏感。课题组前期发现牙槽骨BMSCs存在多个亚群，然而哪一亚群直接响应正畸应力？有待揭示。课题组前期通过构建条件性荧光表达小鼠及单细胞测序发现正畸应力作用下Fat4+细胞亚群比例降低显著；预实验进一步发现该亚群具有多向分化等BMSCs特性，且在应力作用下成骨分化增强明显，可能是一群新的力学敏感细胞。基于以上，提出假设：Fat4+细胞亚群可能是直接响应正畸应力的关键细胞亚群，在应力调控牙槽骨骨改建中发挥重要作用。本项目拟在前期基础上，构建诱导型条件性表达模型，结合谱系示踪、荧光标记、条件性细胞剔除等技术，并进行体内验证，全面系统地研究Fat4+细胞亚群响应正畸应力调控牙槽骨骨改建的机制及其谱系发生，既为正畸应力调控牙槽骨骨改建机理提出新的认识，又为发现新靶点调控骨稳态，开拓新的力学生物学思路。

As the biological basis of clinical orthodontic treatment, the mechanism of mechanical stress-induced alveolar bone remodeling has become the key scientific issue of orthodontics. It has been verified that bone mesenchymal stem cells (BMSCs) are pivotal to bone remodeling and exhibit mechanical sensing properties. Our previous work has revealed that BMSCs are composed of different subpopulations. However, little is known about the critical cell subpopulations that directly interpret mechanical stimuli and enact alveolar bone remodeling. By constructing Osx-Cre conditional tdTomato reporter mouse following with single cell RNA sequencing, we observed a shift in cluster contributions of alveolar bone cells under mechanical stress where the proportion of Fat4+ cells underwent a sharp decrease. Moreover, Fat4+ cells possessed the basic characters of BMSCs and induction of osteogenic differentiation was a notable response of them to mechanical stimuli. Given these results, we hypothesize that Fat4+ cells may be the key BMSCs subpopulation that directly responds to mechanical stress, thus playing an essential role in mechanical stress-induced alveolar bone remodeling. Here, to further investigate the role and lineage hierarchy of Fat4+ cells in alveolar bone remodeling, we intend to construct Fat4-CreERT2 inducible conditional reporter and DTA mouse combined with lineage tracing for both in vivo and in vitro study. This work will not only shed new light on our current understandings of the mechanism of orthodontic tooth movement, but also help to pinpoint potential new clinical applicants for bone homeostasis regulation.