Zhou Yi, Wang Danlei, Xiao Qianxuan, Ma Lu, Gou Huiqing, Ru Yiwen, Tang Jingqi, Xu Xuanwen, Chen Xu, Sun Wen, Li Lu, Xu Yan
Department of Periodontics, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210029, China; State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases (Nanjing Medical University), Nanjing, 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China.
State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases (Nanjing Medical University), Nanjing, 210029, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, China.
Free Radic Biol Med. 2025 Feb 1;227:379-394. doi: 10.1016/j.freeradbiomed.2024.12.016. Epub 2024 Dec 8.
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.
2型糖尿病（T2DM）会加剧牙周疾病损害，而人牙周膜干细胞（PDLSCs）耗竭可能是T2DM损害牙周愈合的关键。本研究旨在探讨糖尿病性牙周炎（DP）中PDLSCs耗竭的机制。首先，我们观察到DP动物模型中牙周破坏加剧，伴有氧化损伤和衰老细胞积累。在体外高糖炎症环境中，我们发现PDLSCs发生衰老、氧化应激、线粒体功能障碍以及由线粒体DNA触发的cGAS-STING信号通路激活。谱系追踪证实，SPD招募Tdtomato-Gli1 PDLSCs至受损区域并减轻DP模型中的牙周破坏。体外证据进一步表明，SPD抑制PDLSCs衰老和氧化应激，增强线粒体功能，减少膜通透性转换孔开放，并减少DNA泄漏，从而阻断STING激活。机制上，SPD通过以线粒体自噬依赖的方式清除线粒体衍生的双链DNA来降低STING-TBK1磷酸化，其治疗效果被STING激活剂cGAMP消除。总之，我们的研究揭示了DP环境中由于过度氧化损伤导致PDLSCs耗竭的机制。局部注射SPD可重新激活线粒体自噬，通过抑制STING激活招募Gli1干细胞促进牙周再生。
