Department of Orthodontics, Peking University School and Hospital of Stomatology, 22# Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
National Engineering Laboratory for Digital and Material Technology of Stomatology, 22# Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
Stem Cell Res Ther. 2020 Mar 13;11(1):112. doi: 10.1186/s13287-020-01607-9.
Tooth movement is a unique bone remodeling process induced by mechanical stimulation. Macrophages are important in mediating inflammatory processes during mechanical load-induced tooth movement. However, how macrophages are regulated under mechanical stimulation remains unclear. Mesenchymal stem cells (MSCs) can modulate macrophage polarization during bone remodeling. Hydrogen sulfide (HS) can be produced by MSCs and have been linked to bone homeostasis. Therefore, this study aimed to investigate whether HS contributed to periodontal ligament stem cell (PDLSC)-regulated macrophage polarization and bone remodeling under mechanical stimulation.
An experimental mechanical load-induced tooth movement animal model was established. Changes in cystathionine-β-synthase (CBS), markers of M1/M2 macrophages, tooth movement distance, and the number of osteoclasts were examined. The conditioned medium of PDLSCs with or without mechanical loading was utilized to treat THP-1 derived macrophages for 24 h to further investigate the effect of PDLSCs on macrophage polarization. Different treatments with HS donor, CBS inhibitor, or the inhibitor of STAT1 were used to investigate the related mechanism. Markers of M1/M2 polarization and STAT1 pathway expression were evaluated in macrophages.
Mechanical load promoted tooth movement and increased the number of M1-like macrophages, M1-associated pro-inflammatory cytokines, and the expression of CBS on the compression side of the periodontal ligament. The injection of CBS inhibitor or HS donor could further repress or increase the number of M1-like macrophages, tartrate-resistant acid phosphatase-positive osteoclasts and the distance of tooth movement. Mechanistically, load-induced PDLSCs enhanced HS production, which increased the expression of M1-associated cytokines in macrophages. These effects could be blocked by the administration of CBS inhibitor. Moreover, load-induced HS steered M1 macrophage polarization via the STAT1 signaling pathway.
These data suggest a novel mechanism indicating that mechanical load-stimulated PDLSCs produce HS to polarize macrophages toward the M1 phenotype via the STAT1 signaling pathway, which contributes to bone remodeling and tooth movement process. These results provide new insights into the role of PDLSCs in regulating macrophage polarization and mediating bone remodeling under mechanical stimulation, and indicate that appropriate HS supplementation may accelerate tooth movement.
牙齿移动是一种由机械刺激诱导的独特的骨重塑过程。巨噬细胞在机械负荷诱导的牙齿移动过程中的炎症反应中起重要作用。然而，巨噬细胞在机械刺激下是如何被调节的还不清楚。间充质干细胞（MSCs）可以在骨重塑过程中调节巨噬细胞的极化。硫化氢（HS）可以由 MSCs 产生，并与骨稳态有关。因此，本研究旨在探讨 HS 是否有助于牙周膜干细胞（PDLSC）在机械刺激下调节巨噬细胞极化和骨重塑。
建立了实验性机械负荷诱导的牙齿移动动物模型。检测胱硫醚-β-合酶（CBS）、M1/M2 巨噬细胞标志物、牙齿移动距离和破骨细胞数量的变化。用机械加载或不加载的 PDLSC 条件培养基处理 THP-1 来源的巨噬细胞 24 小时，进一步研究 PDLSC 对巨噬细胞极化的影响。用 HS 供体、CBS 抑制剂或 STAT1 抑制剂进行不同处理，以探讨相关机制。在巨噬细胞中评估 M1/M2 极化和 STAT1 通路表达的标志物。
机械负荷促进牙齿移动，并增加了牙周韧带压缩侧 M1 样巨噬细胞、M1 相关促炎细胞因子和 CBS 的数量。CBS 抑制剂或 HS 供体的注射可进一步抑制或增加 M1 样巨噬细胞、抗酒石酸酸性磷酸酶阳性破骨细胞的数量和牙齿移动的距离。机制上，负荷诱导的 PDLSCs 增强了 HS 的产生，从而增加了巨噬细胞中 M1 相关细胞因子的表达。这些作用可以被 CBS 抑制剂阻断。此外，负荷诱导的 HS 通过 STAT1 信号通路引导 M1 巨噬细胞极化。
这些数据表明了一种新的机制，即机械负荷刺激的 PDLSCs 产生 HS，通过 STAT1 信号通路使巨噬细胞向 M1 表型极化，从而促进骨重塑和牙齿移动过程。这些结果为 PDLSCs 在机械刺激下调节巨噬细胞极化和介导骨重塑中的作用提供了新的见解，并表明适当的 HS 补充可能加速牙齿移动。
