Wang Hao, Gao Yu-Cheng, Dai Guang-Chun, Lu Pan-Pan, Li Ying-Juan, Cao Mu-Min, Liu Xiao-Yu, Sheng Ren-Wang, Shi Liu, Zhang Cheng, Cui Wen-Guo, Rui Yun-Feng
Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China.
Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.
J Adv Res. 2025 Aug 11. doi: 10.1016/j.jare.2025.08.013.
Aged tendon exhibits impaired regenerative capacity due to the accumulation of senescent tendon stem/progenitor cells (TSPCs), which secrete senescence-associated secretory phenotype (SASP) factors and display compromised differentiation. Despite its clinical significance in recurrent tendon injury, no targeted therapies exist to counteract TSPCs senescence.
This study aimed to investigate the anti-senescent effects of quercetin on TSPCs through a mechanistic exploration of the AKT/mitochondrial/SASP axis and to develop a dipeptide-hydrogel delivery system (DPH@QUE) for the localized treatment of age-related tendon injury.
Senescent TSPCs were treated with quercetin in vitro to assess SASP reduction and tenogenic differentiation via molecular profiling. Mechanistically, AKT phosphorylation and mitochondrial function were analyzed. In vivo, DPH@QUE was administered to aged rat Achilles tendon injury models, with histopathological and functional evaluations conducted at 8 weeks post-intervention.
Quercetin significantly alleviated senescence in TSPCs, as evidenced by decreased secretion of SASP and enhanced tenogenic differentiation. Mechanistically, the inhibition of AKT phosphorylation ameliorated mitochondrial dysfunction and suppressed SASP secretion by modulating the NF-κB/NLRP3 signaling axis, thereby attenuating TSPCs senescence. Furthermore, the sustained release of quercetin using a dipeptide hydrogel into the site of Achilles tendon injury in elderly rats produced exceptional anti-inflammatory and reparative effects, effectively restoring endogenous tendon regeneration.
Our findings suggest quercetin could alleviate senescent phenotypes in TSPCs through AKT-mediated mitochondrial stabilization and SASP suppression. The DPH@QUE delivery system enables effective translation of these anti-aging effects into functional tendon regeneration, providing a novel therapeutic strategy for aging tendon injury.
由于衰老的肌腱干/祖细胞（TSPCs）积累，老化的肌腱表现出再生能力受损，这些细胞分泌衰老相关分泌表型（SASP）因子并显示出受损的分化能力。尽管其在复发性肌腱损伤中具有临床意义，但目前尚无针对性疗法来对抗TSPCs衰老。
本研究旨在通过对AKT/线粒体/SASP轴的机制探索，研究槲皮素对TSPCs的抗衰老作用，并开发一种二肽水凝胶递送系统（DPH@QUE）用于局部治疗与年龄相关的肌腱损伤。
在体外用槲皮素处理衰老的TSPCs，通过分子分析评估SASP减少和肌腱生成分化情况。从机制上分析AKT磷酸化和线粒体功能。在体内，将DPH@QUE给予老年大鼠跟腱损伤模型，在干预后8周进行组织病理学和功能评估。
槲皮素显著减轻了TSPCs的衰老，表现为SASP分泌减少和肌腱生成分化增强。从机制上讲，抑制AKT磷酸化可改善线粒体功能障碍，并通过调节NF-κB/NLRP3信号轴抑制SASP分泌，从而减轻TSPCs衰老。此外，使用二肽水凝胶将槲皮素持续释放到老年大鼠跟腱损伤部位产生了显著的抗炎和修复作用，有效地恢复了内源性肌腱再生。
我们的研究结果表明，槲皮素可通过AKT介导的线粒体稳定和SASP抑制减轻TSPCs的衰老表型。DPH@QUE递送系统能够将这些抗衰老作用有效地转化为功能性肌腱再生，为衰老性肌腱损伤提供了一种新的治疗策略。
