Spermidine alleviates diabetic periodontitis by reversing human periodontal ligament stem cell senescence via mitophagy

Type 2 Diabetes Mellitus (T2DM) exacerbates periodontal disease lesions, and human periodontal ligament stem cells (PDLSCs) depletion may be the key to periodontal healing impair by T2DM. This study aims to explore the mechanism of PDLSCs depletion in diabetes periodontitis (DP). Firstly, we observed aggravated periodontal destruction in the DP animal model, accompanied by oxidative damage and accumulation of senescent cells. In the high-glucose inflammatory environment in vitro, we revealed that PDLSCs underwent senescence, oxidative stress, mitochondrial dysfunction, and activation of cGAS-STING signaling pathway triggered by mitochondrial DNA. Lineage tracing confirmed that SPD recruited Tdtomato-Gli1+ PDLSCs to the damaged area and alleviated periodontal destruction in DP models. Evidence in vitro further showed that SPD inhibited PDLSCs senescence and oxidative stress, enhanced mitochondrial function, reduced membrane permeability transition pore opening, and reduced DNA leakage, which blocked the STING activation. Mechanistically, SPD reduced STING-TBK1 phosphorylation by scavenging mitochondrial-derived dsDNA in a mitophagy-dependent manner, its therapeutic effect was abolished by incorporation of cGAMP, a STING activator. In summary, our study reveals the mechanism of PDLSCs depletion due to excessive oxidative damage in the DP environment. Local injection of SPD reactivates mitophagy, recruits Gli1+ stem cells by inhibiting STING activation for periodontal regeneration. [Display omitted] •High glucose inflammatory environment induced senescence of periodontal ligament stem cells.•Mitochondrial DNA release due to oxidative stress activates the STING-TBK1 signaling axis in PDLSCs.•Spermidine activates mitophagy to remove free mitochondrial DNA and mitigates mitochondrial oxidative stress.•Spermidine recruits Gli1-positive stem cells to participate in tissue regeneration in diabetic periodontitis.