Abstract
BackgroundThe use of adipose-derived mesenchymal stromal 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.MethodsThe adipose-derived mesenchymal stromal cells (ADSCs) and tendon stem cells (TSCs) were isolated from the 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 the 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.ResultsADSC-Exos could be absorbed by TSCs and promoted the proliferation, migration, and tenogenic differentiation of these cells. This effect may have depended on the activation of the SMAD2/3 and SMAD1/5/9 pathways. Furthermore, ADSC-Exos inhibited the early inflammatory reaction and promoted tendon healing in vivo.ConclusionsOverall, we demonstrated that ADSC-Exos contributed to tendon regeneration and provided proof of concept of a new approach for treating tendon injuries.
Highlights
Tendon is a dense connective tissue consisting of limited tendon cells and abundant extracellular matrix (ECM)
adipose-derived mesenchymal stromal cells (ADSCs)-Exos regulated tendon stem cells (TSCs) proliferation, migration, and tenogenic differentiation by activating SMAD2/3 and SMAD1/5/9 signaling pathways To investigate the regulatory effect of ADSC-Exos, we evaluated their effects on the proliferation, migration, and tendon differentiation of TSCs by pretreating them with SB431542 or dorsomorphin
ADSC-Exos regulated the early inflammatory response during tendon healing We investigated the in vivo effect of ADSC-Exos on early healing of tendon injury
Summary
Tendon is a dense connective tissue consisting of limited tendon cells and abundant extracellular matrix (ECM). Tendon healing is slow as a result of its hypocellularity and hypovascularity and involves three overlapping phases: inflammation, proliferation, and remodeling [2, 3]. The self-healing potential of any tissue depends, in part, on its endogenous resident stem cells. The viability and tenogenic differentiation of tendon stem cells (TSCs) are the main mechanisms of tendon repair [4]. It is important to enhance tendon healing by promoting anti-inflammation and the proliferation of TSCs. The use of adipose-derived mesenchymal stromal cell-derived exosomes (ADSC-Exos) may become a new therapeutic method in biomedicine owing to their important role in regenerative medicine. The role of ADSC-Exos in tendon repair has not yet been evaluated. We aimed to clarify the healing effects of ADSC-Exos on tendon injury
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