Spermidine suppresses PDLSCs aging in periodontitis with T2DM via mitophagy

The healing of periodontal tissue in periodontitis is affected by many factors. Multiple evidences suggest that type 2 diabetes mellitus affects the healing of periodontal tissue, but the exact mechanism is still unclear. Among the many possible causes, stem cell depletion caused by oxidative stress may be the key to periodontal tissue regeneration. Periodontal ligament stem cells (PDLSCs) play an indispensable role in periodontal regeneration. In this study, we observed oxidative damage, DNA leakage and cell senescence in the periodontal tissues in animal models. We characterized the aging properties of human periodontal ligament stem cells (hPDLSCs) in an in vitro high glucose inflammatory model, revealing cGAS-STING signaling activated by oxidized mitochondrial DNA (mtDNA). Our study demonstrated that spermidine (SPD) could inhibit STING signaling by reducing the abundance of oxidized mtDNA through activating mitophagy, which could inhibit hPDLSCs senescence. Furthermore, using Gli1-tdTomato stem cell tracing animal model, we demonstrated that local application of SPD could promote the recruitment of Gli1+ PDLSCs to the lesion area. SPD significantly abolished oxidative stress in periodontitis tissues accompanying T2D and promoted periodontal regeneration. This study revealed the mechanism of impaired periodontal regeneration caused by T2D from the perspective of cellular senescence, and screened spermidine as a promising agent for promoting periodontal regeneration. The healing of periodontal tissue in periodontitis is affected by many factors. Multiple evidences suggest that type 2 diabetes mellitus affects the healing of periodontal tissue, but the exact mechanism is still unclear. Among the many possible causes, stem cell depletion caused by oxidative stress may be the key to periodontal tissue regeneration. Periodontal ligament stem cells (PDLSCs) play an indispensable role in periodontal regeneration. In this study, we observed oxidative damage, DNA leakage and cell senescence in the periodontal tissues in animal models. We characterized the aging properties of human periodontal ligament stem cells (hPDLSCs) in an in vitro high-glucose-induced inflammation model, revealing cGAS-STING signaling activated by oxidized mitochondrial DNA (mtDNA). Our study demonstrated that spermidine (SPD) could inhibit STING signaling by reducing the abundance of oxidized mtDNA through activating mitophagy, which could inhibit hPDLSCs senescence. Furthermore, using Gli1-tdTomato stem cell tracing animal model, we demonstrated that local application of SPD could promote the recruitment of Gli1+ PDLSCs to the lesion area. SPD significantly abolished oxidative stress in periodontitis tissues accompanying T2D and promoted periodontal regeneration. This study revealed the mechanism of impaired periodontal regeneration caused by T2D from the perspective of cellular senescence, and screened spermidine as a promising agent for promoting periodontal regeneration.