Tendon-derived extracellular vesicles enhance TDSC activity and alleviate inflammatory response: a pathway to promote tendon regeneration

Tendon-derived stem cells (TDSCs) are pivotal in tendon regeneration, yet their therapeutic potential is hindered by inherent challenges such as erroneous differentiation and functional impairment under oxidative stress and inflammatory conditions. Recent studies have highlighted the potential of extracellular vesicles (EVs) as a promising therapeutic strategy to address these challenges and enhance tendon regeneration. This study investigated the effects of tendon-derived extracellular vesicles (tEVs) on the functionality of TDSCs, with a specific focus on the regulatory roles of tEVs in TDSC proliferation, migration, tenogenic differentiation, and modulation of the immune microenvironment. <i>In vitro</i> experiments revealed that tEVs significantly enhanced TDSC proliferation and migration, upregulated the mRNA and protein expression of key growth factors such as hepatocyte growth factor (HGF) and insulin-like growth factor 1(IGF-1), and facilitated their differentiation into mature tenocytes. Furthermore, tEVs were found to alleviate IL-1β-induced inflammatory responses by reducing levels of proinflammatory cytokine (TNF-α and IL-6), alleviating oxidative stress and mitochondrial damage. In conclusion, tEVs enhance the functionality of TDSCs through two primary mechanisms: enhancing TDSC activity and modulating the immune microenvironment. These findings provide novel theoretical insights and highlight potential translational strategies for applying cell-free therapies for tendon regeneration.