Dendritic Cell-Derived Exosomes Promote Tendon Healing and Regulate Macrophage Polarization in Preventing Tendinopathy

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Abstract
Introduction: Tendon injuries present a significant challenge for independent repair, and can progress into tendinopathy over time, highlighting the importance of early intervention. Dendritic cell-derived exosomes (DEXs) has been shown to shift the polarization of M1 macrophages, the predominant inflammatory cells in the early stages of tendon injury. This study introduces a therapeutic approach that effectively manages inflammation while promoting regeneration in the treatment of tendinopathy. Methods: The purification and characterization of DEXs were meticulously conducted. Experiments were carried out using an Achilles tendon rupture mouse model, with weekly DEXs treatment starting on postoperative day (POD) 4. In vitro, the function of DEXs was assessed by coculturing them with tendon stem/progenitor cells (TSPCs) in culture medium containing IL-1β. Tendon healing progress was evaluated using Sirius Red staining, Masson’s trichrome staining, biomechanical testing, and immunofluorescence microscopy. The inflammatory microenvironment of injured tendons was evaluated using the Luminex procedure and flow cytometry analysis. Results: DEXs treatment significantly enhanced tendon cell differentiation, promoted collagen type I synthesis, and inhibited collagen type III synthesis, thereby expediting tendon healing. Furthermore, DEXs treatment improved the inflammatory microenvironment by reducing multiple cytokines (IL-1β, IL-4, IL-6, TNF-α, and IFN-γ) and induced the conversion of M1 macrophages to M2 macrophages by activating the PI3K/AKT pathway. Conclusion: DEXs demonstrated a potent ability to promote tendon healing while ameliorating the inflammatory microenvironment, suggesting their potential as a therapeutic approach to prevent the development of tendinopathy.

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