MiR-21/自噬环路响应力学信号调控牙周膜干细胞功能在正畸所致牙周改建中的作用研究

Mechanical signal induced the regeneration of periodontium is the foundation of orthodontic tooth movement (OTM). Plenty researches reported that the periodontal ligament stem cells (PDLSCs) is the critical cell of the perodontium regeneration. Our previous study revealed that the mechanical signal could affect the function of PDLSCs and thus caused the regeneration of periodontium. However, the mechanism of how mechanical signal regulates the function of PDLSCs remains elusive. Previous miRNA array showed that miR-21 expression was significantly changed with mechanical signal. Furthermore, we found that the authphagy level was closed to the function of PDLSCs and direct proportion to miR-21 expression after exposure to mechanical signal. Therefore, we infer that the miR-21/autophagy cascade may play an important role in PDLSCs reponsed to mechanical signal. In this study, we using miR-21 knockout mice, gene transfection, luciferase reporter gene detection to investigate the regulatory role of how miR-21/autophagy cascade in PDLSCs-mediated the regeneration of periodontium. Our study firstly reveals the role of miR-21/autophagy in periodontal regeneration and provides a new regulation target for clinical OTM.

牙周组织改建是正畸牙移动的基础，牙周膜干细胞（PDLSCs）被证明在维持牙周组织稳态中发挥至关重要的作用。而力学信号如何调控PDLSCs功能目前仍不明确。我们前期研究发现加力后PDLSCs中miR-21表达升高最为显著，而miR-21敲除小鼠则牙移动困难。研究表明，自噬是促进PDLSCs成骨分化的重要原因。我们前期证明炎性微环境中PDLSCs自噬升高，同时其抑制剂能明显抑制PDLSCs成骨分化。因此，我们推测miR-21可能通过调控自噬影响PDLSCs的功能。本项目拟探索力学信号对PDLSCs自噬水平的影响，解析力学信号通过miR-21调控PDLSCs自噬的分子机制，并利用模式小鼠验证miR-21、自噬和牙周改建的关系。本项目从以上三方面探讨表观遗传、自噬及正畸牙周改建之间关系，首次揭示正畸力可通过microRNA调控细胞自噬水平的分子机制，为临床中调控牙周组织改建提供靶点依据和实验基础。

正畸牙移动是牙周组织通过一系列生理反应发生骨改建的过程，然而正畸牙移动过程中力学信号如何调控牙周改建的具体机制尚不明确。本课题根据前期研究推测力学信号可能通过miR-21调控PDLSCs自噬及其再生能力进而影响正畸牙移动。体外PDLSCs拉力和压力模型及体内小鼠正畸牙移动模型的自噬相关检测揭示了自噬调控PDLSC功能、骨改建和响应力学信号的关键作用。接着我们进一步引入了miR-21基因敲除小鼠模型及MSC-OC共培养加力体系，解析了力学信号通过miR-21调控自噬促OC活化参与骨改建的重要机制，并且发现删除内源PDLSCs、敲除miR-21或抑制自噬均可有效抑制正畸牙移动。本课题首次揭示正畸力可以通过microRNA调控细胞自噬水平的分子机制，为临床中调控牙周组织改建提供靶点依据和实验基础。同时因为表观遗传调控的存在，使得牙周改建是一个持续过程，也为解释正畸的复发机制提供了一定的参考，具有重要的理论与临床意义。