The treatment of acute tendon injury with small extracellular vesicles originating from TNFAIP6(-) ADSCs subpopoulation both in vitro and in vivo.

BACKGROUND: Small extracellular vesicles originating from adipose-derived mesenchymal stromal cells (ADSC-sEVs) have excellent therapeutic value in acute tendon injury. However, their mechanism and effects have not been fully elucidated. This study aimed to identify the key subsets and mechanisms of action of ADSC-sEVs involved in the repair of complete tendon tear caused by acute injury. METHODS: Based on our previous research demonstrating that ADSC-sEVs improve the quality of acute tendon injury repair, the present study utilized second-generation sequencing and bioinformatics to predict the key role of the TNFAIP6(-) ADSC subgroup in acute tendon injury repair. We constructed different ADSC-sEVs through ADSC transfection and treated tendon stem cells for further exploration. EdU, cell scratch, and Transwell assays were used to evaluate cell proliferation and migration in vitro. Western blot and quantitative real-time polymerase chain reaction analyses were performed. Histopathological, immunohistochemical, and biomechanical testing were used for in vivo validation. RESULTS: TNFAIP6(-) ADSC-sEVs significantly improved the therapeutic effect of ADSC-sEVs on acute tendon injury, which was related to the high expression of let-7c-5p. Application of different ADSC-sEVs in vitro and in vivo identified CRCT1/JAK2/STAT3 as a key downstream signaling pathway regulated by let-7c-5p. CONCLUSIONS: Our findings enhance the current understanding of how TNFAIP6(-) ADSC-sEVs exert healing properties in acute tendon injury through the let-7c-5p/CRCT1/JAK2/STAT3 signaling pathway. Furthermore, this study proposes a concept for constructing conditional ADSC-sEVs to enhance their inherent therapeutic effects.