Human bone marrow mesenchymal stem cell-derived extracellular vesicles inhibit shoulder stiffness via let-7a/Tgfbr1 axis

Bioactive Materials

Yuzhen Xu¹  Yisheng Chen²  Beijie Qi²  Jinrong Lin²  Zhiwen Luo²  Yaying Sun²  Jiwu Chen³ 

[1] Department of Rehabilitation, The Second Affiliated Hospital of Shandong First Medical University, Shandong Province, China;Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China;Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;

关键词: Shoulder stiffness;    Adhesive capsulitis;    Extracellular vesicles;    Human bone marrow mesenchymal stem cell;    MicroRNA;    Fibrosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

Shoulder stiffness (SS) is a common shoulder disease characterized by increasing pain and limited range of motion. SS is considered to be an inflammatory and fibrotic disorder pathologically. However, there is no consensus on the most effective conservative treatment for fibrosis. Given that human Bone Marrow Mesenchymal Stem Cell-derived extracellular vesicles (BMSC-EVs) displayed promising therapeutic effects for various tissues, we investigated the therapeutic effect of BMSC-EVs on fibrosis in a mice immobilization model and two cell models. By conducting a series of experiments, we found that BMSC-EVs can significantly inhibit the fibrogenic process both in vitro and in vivo. In detail, BMSC-EVs suppressed the aberrant proliferation, high collagen production capacity, and activation of fibrotic pathways in TGF-β-stimulated fibroblasts in vitro. Besides, in vivo, BMSC-EVs reduced cell infiltration, reduced fibrotic tissue in the shoulder capsule, and improved shoulder mobility. In addition, via exosomal small RNA sequencing and qPCR analysis, let-7a-5p was verified to be the highest expressed miRNA with predicted antifibrotic capability in BMSC-EVs. The antifibrotic capacity of BMSC-EVs was significantly impaired after the knockdown of let-7a-5p. Moreover, we discovered that the mRNA of TGFBR1 (the membrane receptor of transforming growth factor β) was the target of let-7a-5p. Together, these findings elucidated the antifibrotic role of BMSC-EVs in shoulder capsular fibrosis. This study clarifies a new approach using stem cell-derived EVs therapy as an alternative to cell therapy, which may clinically benefit patients with SS in the future.

【 授权许可】

Unknown