Mechanical load-induced H ₂S production by periodontal ligament stem cells activates M1 macrophages to promote bone remodeling and tooth movement via STAT1

Abstract

Background

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 (H ₂S) can be produced by MSCs and have been linked to bone homeostasis. Therefore, this study aimed to investigate whether H ₂S contributed to periodontal ligament stem cell (PDLSC)-regulated macrophage polarization and bone remodeling under mechanical stimulation.

Methods

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 H ₂S 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.

Results

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 H ₂S 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 H ₂S 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 H ₂S steered M1 macrophage polarization via the STAT1 signaling pathway.

Conclusions

These data suggest a novel mechanism indicating that mechanical load-stimulated PDLSCs produce H ₂S 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 H ₂S supplementation may accelerate tooth movement.

Electronic supplementary material

Supplementary information accompanies this paper at 10.1186/s13287-020-01607-9.