MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling
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 sol...
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| Format: | Article |
| Language: | English |
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BMC
2021-06-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-021-00906-4 |
| _version_ | 1811186638705917952 |
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| author | Zhixiao Yao Juehong Li Hao Xiong Haomin Cui Jiexin Ning Shikun Wang Xingyu Ouyang Yun Qian Cunyi Fan |
| author_facet | Zhixiao Yao Juehong Li Hao Xiong Haomin Cui Jiexin Ning Shikun Wang Xingyu Ouyang Yun Qian Cunyi Fan |
| author_sort | Zhixiao Yao |
| collection | DOAJ |
| description | 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. Graphic abstract |
| first_indexed | 2024-04-11T13:49:31Z |
| format | Article |
| id | doaj.art-bd3524a6e6684a21a2e860e20b22c94f |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-11T13:49:31Z |
| publishDate | 2021-06-01 |
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| series | Journal of Nanobiotechnology |
| spelling | doaj.art-bd3524a6e6684a21a2e860e20b22c94f2022-12-22T04:20:48ZengBMCJournal of Nanobiotechnology1477-31552021-06-0119111810.1186/s12951-021-00906-4MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signalingZhixiao Yao0Juehong Li1Hao Xiong2Haomin Cui3Jiexin Ning4Shikun Wang5Xingyu Ouyang6Yun Qian7Cunyi Fan8Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Plastics, Binzhou People’s HospitalDepartment of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalAbstract 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. Graphic abstracthttps://doi.org/10.1186/s12951-021-00906-4Tendon repairHuman umbilical cord mesenchymal stem cellExosomePTENmTORmiR-29a-3p |
| spellingShingle | Zhixiao Yao Juehong Li Hao Xiong Haomin Cui Jiexin Ning Shikun Wang Xingyu Ouyang Yun Qian Cunyi Fan MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling Journal of Nanobiotechnology Tendon repair Human umbilical cord mesenchymal stem cell Exosome PTEN mTOR miR-29a-3p |
| title | MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling |
| title_full | MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling |
| title_fullStr | MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling |
| title_full_unstemmed | MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling |
| title_short | MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling |
| title_sort | microrna engineered umbilical cord stem cell derived exosomes direct tendon regeneration by mtor signaling |
| topic | Tendon repair Human umbilical cord mesenchymal stem cell Exosome PTEN mTOR miR-29a-3p |
| url | https://doi.org/10.1186/s12951-021-00906-4 |
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