Adipose-derived Mesenchymal Stem Cell-derived Exosomes Promote Tendon Healing by Activating Both SMAD1/5/9 and SMAD2/3

Abstract

\n Background: The use of adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) may become a new therapeutic method in biomedicine owing to their important role in regenerative medicine. However, the role of ADSC-Exos in tendon repair has not yet been evaluated. Therefore, we aimed to clarify the healing effects of ADSC-Exos on tendon injury.Methods: The adipose-derived mesenchymal stem cells (ADSCs) and tendon stem cells (TSCs) were isolated from subcutaneous fat and tendon tissues of Sprague Dawley rats, respectively, and exosomes were isolated from ADSCs. The proliferation and migration of TSCs induced by ADSC-Exos were analyzed by EdU, cell scratch and transwell assays. We used western blot to analyze tenogenic differentiation of TSCs and the role of the SMAD signaling pathways. Then we explored a new treatment method for tendon injury, combining exosome therapy with local targeting using a biohydrogel. Immunofluorescence and immunohistochemistry were used to detect the expression of inflammatory and tenogenic differentiation after tendon injury, respectively. The quality of tendon healing was evaluated by Hematoxylin-eosin (H&E) staining and biomechanical testing.Results: ADSC-Exos could be absorbed by TSCs, and promoted the proliferation, migration, and tenogenic differentiation of these cells. This effect may have depended on activation of the SMAD2/3 and SMAD1/5/9 pathways. Furthermore, ADSC-Exos inhibited the early inflammatory reaction and promoted tendon healing in vivo.Conclusions: Overall, we demonstrated that ADSC-Exos contributed to tendon regeneration and provided proof of concept of a new approach for treating tendon injuries.