Quercetin attenuates tendon stem/progenitor cell senescence and promotes aged tendon repair via AKT/NF-κB/NLRP3-mediated mitophagy activation

Abstract

Introduction: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Cellular senescence; Inflammation; SASP; Tendon aging; Tendon stem/progenitor cells.