Zhixiao Yao1, Juehong Li1, Hao Xiong1, Haomin Cui1, Jiexin Ning2, Shikun Wang1, Xingyu Ouyang1, Yun Qian3, Cunyi Fan4. 1. Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. 2. Department of Plastics, Binzhou People's Hospital, Binzhou, 256610, China. 3. Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. lollipopcloudland@foxmail.com. 4. Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. cyfan@sjtu.edu.cn.
Abstract
BACKGROUND: Exosomes 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. RESULTS: Expression 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. CONCLUSION: The 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.
BACKGROUND: Exosomes 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. RESULTS: Expression of tendon-specific markers in, and collagen deposition by, tendon-derived stem cells (TDSCs) treated with HUMSC-Exos increased in vitro. In a ratAchilles 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. CONCLUSION: The 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.
Authors: Yalin Zhang; Min Soo Kim; Baosen Jia; Jingqi Yan; Juan Pablo Zuniga-Hertz; Cheng Han; Dongsheng Cai Journal: Nature Date: 2017-07-26 Impact factor: 49.962
Authors: Julianne Huegel; Peter Y W Chan; Stephanie N Weiss; Courtney A Nuss; Harina Raja; Erik I Waldorff; Nianli Zhang; James T Ryaby; Louis J Soslowsky; Andrew F Kuntz Journal: J Orthop Res Date: 2021-10-17 Impact factor: 3.102
Authors: Luciano C Ramires; Madhan Jeyaraman; Sathish Muthu; Navaladi Shankar A; Gabriel Silva Santos; Lucas Furtado da Fonseca; José Fábio Lana; Ramya Lakshmi Rajendran; Prakash Gangadaran; Manasi P Jogalekar; Alfredo A Cardoso; Alex Eickhoff Journal: Life (Basel) Date: 2022-03-09