MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling

Journal of Nanobiotechnology

Haomin Cui¹  Juehong Li¹  Zhixiao Yao¹  Xingyu Ouyang¹  Hao Xiong¹  Yun Qian¹  Shikun Wang¹  Cunyi Fan¹  Jiexin Ning² 

[1] Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 200233, Shanghai, China;Department of Plastics, Binzhou People’s Hospital, 256610, Binzhou, China;

关键词: Tendon repair;    Human umbilical cord mesenchymal stem cell;    Exosome;    PTEN;    mTOR;    miR-29a-3p;   

DOI  :  10.1186/s12951-021-00906-4

来源: Springer

【 摘 要 】

BackgroundExosomes are extracellular vesicles of nano-structures and represent an emerging nano-scale acellular therapy in recent years. Tendon regeneration is a sophisticated process in the field of microsurgery due to its poor natural healing ability. To date, no successful long-term solution has been provided for the healing of tendon injuries. Functional recovery requires advanced treatment strategies. Human umbilical cord mesenchymal stem cell-derived exosomes (HUMSC-Exos) are considered as promising cell-free therapeutic agents. However, few studies reported their potential in the tendon repair previously. In this study, we explored the roles and underlying mechanisms of HUMSC-Exos in the tendon regeneration.ResultsExpression of tendon‐specific markers in, and collagen deposition by, tendon-derived stem cells (TDSCs) treated with HUMSC-Exos increased in vitro. In a rat Achilles tendon injury model, treatment with HUMSC-Exos improved the histological structure, enhanced tendon-specific matrix components, and optimized biomechanical properties of the Achilles tendon. Findings in miRNA sequencing indicated a significant increase in miR-29a-3p in HUMSC-Exo-treated Achilles tendons. Next, luciferase assay in combination with western blot identified phosphatase and tensin homolog (PTEN) as the specific target of miR-29a-3p. Furthermore, we applied a miR-29a-3p-specific agonist to engineer HUMSC-Exos. These HUMSC-Exos overexpressing miR-29a-3p amplified the gain effects of HUMSC-Exos on tendon healing in vivo. To explore the underlying mechanisms, a transforming growth factor-β1 (TGF-β1) inhibitor (SB-431542), mTOR inhibitor (rapamycin), and engineered HUMSC-Exos were employed. The results showed that TGF-β1 and mTOR signaling were involved in the beneficial effects of HUMSC-Exos on tendon regeneration.ConclusionThe findings in our study suggest that PTEN/mTOR/TGF-β1 signaling cascades may be a potential pathway for HUMSC-Exos to deliver miR-29a-3p for tendon healing and implicate a novel therapeutic strategy for tendon regeneration via engineered stem cell-derived exosomes.Graphic abstract

【 授权许可】

CC BY