Adipose Stem Cell-Derived Exosomes As a Macrophage-Based Treatment for Chronic Rotator Cuff Tendinopathy: From a Mouse Model to a Study in Human Tissue

OBJECTIVES: Chronic rotator cuff tendinopathy is one of the most prevalent causes of shoulder pain. Growing evidence suggests that macrophages play a significant role in the pathogenesis of tendinopathy. Therefore, a treatment that targets macrophages would be useful for patients with this common musculoskeletal disorder. To investigate whether adipose stem cell-derived exosomes (ASC-Exos) mediate polarization of macrophages and contribute to the healing of chronic rotator cuff tendinopathy. METHODS: First, we compared the effects of ASC-Exos on polarization of mouse bone marrow-derived macrophages between a classically activated phenotype (M1φ) and an alternatively activated phenotype (M2φ) in vitro. Seventy-two C57Bl/6 mice were assigned to normal cage activity (n=24) or 5 weeks of treadmill overuse (n=48). The enthesis of supraspinatus in each mouse was then injected with ASC-Exos (ASC-Exos group, n=24) or saline (saline group, n=24). Histological and biomechanical outcomes were assessed 4 weeks after treatment. Finally, tissue samples from human patients with rotator cuff tendinopathy were obtained to determine the effect of ASC-Exos on the M1φ/M2φ balance in tissue-resident macrophages. RESULTS: ASC-Exos inhibited M1φ polarization and augmented M2φ polarization both in mouse bone marrow-derived macrophages, mouse in vivo model and human tissue-resident macrophages. Mice in the ASC-Exos group showed less severe pathological changes than the saline group, including less cellular infiltration, disorganization of collagen, and ground substance deposition. The mean modified Bonar score was significantly lower in the ASC-Exos group than in the saline group (9.81 ± 0.96 vs 7.69 ± 1.03; P<.05). Furthermore, the maximum failure load was significantly higher in the ASC-Exos group than in the saline group (4.23 ± 0.66 N vs 3.86 ± 0.65 N; P<.05) as was stiffness (3.38 ± 0.34 N/m vs. 2.68 ± 0.49 N/m; P<.05). CONCLUSIONS: ASC-Exos-mediated balance of M1φ/M2φ contributes to healing of tendinopathy. Regulation of the M1φ/M2φ balance could be a new target for treatment of chronic rotator cuff tendinopathy.