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

Yao, Zhixiao, Li, Juehong, Xiong, Hao, Cui, Haomin, Ning, Jiexin, Wang, Shikun, Ouyang, Xingyu, Qian, Yun, Fan, Cunyi·2021·Journal of Nanobiotechnology
DOI 10.1186/s12951-021-00906-4PMC PMC8180131
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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:

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Fig. 1 Identification of exosomes and TDSCs. A Representative image of HUMSC-Exos observed by electron microscopy. Scale bar: 200 nm. B NTA observation of the size of the HUMSC-Exos. C Surface markers of HUMSCs and HUMSC-Exos measured using western blot. D Cellular uptake of HUMSC-Exos by TDSCs observed using PKH67 staining, scale bar: 20 μm. E Flow cytometry analysis of the surface antigens of TDSCs (n = 5 per group). TDSCs could differentiate into osteoblasts, adipocytes, and chondrocytes. F Alizarin Red S staining, scale bar: 50 μm. G Oil Red O staining, scale bar: 25 μm. H Alcian Blue staining, scale bar: 25 μm
Fig. 1 Identification of exosomes and TDSCs. A Representative image of HUMSC-Exos observed by electron microscopy. Scale bar: 200 nm. B NTA observation of the size of the HUMSC-Exos. C Surface markers of HUMSCs and HUMSC-Exos measured using western blot. D Cellular uptake of HUMSC-Exos by TDSCs observed using PKH67 staining, scale bar: 20 μm. E Flow cytometry analysis of the surface antigens of TDSCs (n = 5 per group). TDSCs could differentiate into osteoblasts, adipocytes, and chondrocytes. F Alizarin Red S staining, scale bar: 50 μm. G Oil Red O staining, scale bar: 25 μm. H Alcian Blue staining, scale bar: 25 μmCC BY · PubMed Central
Fig. 2 HUMSC-Exos promoted expression of tendon markers. A Representative cellular immunofluorescence images of COL1A1, COL3A1, DCN, TNMD (red), and the nuclei stained with DAPI (blue), scale bar: 50 μm. B–E Quantification of cellular immunofluorescence (n = 6 per group). *P < 0.05 vs. control. #P < 0.05 vs. Sup group. F Representative western blot images of COL1A1, COL3A1, MKX, SCXA, DCN, and TNMD. G, H. Sirius Red staining for collagen deposition (n = 6 per group). ***P < 0.001 vs. control group. ###P < 0.001 vs. Sup group
Fig. 2 HUMSC-Exos promoted expression of tendon markers. A Representative cellular immunofluorescence images of COL1A1, COL3A1, DCN, TNMD (red), and the nuclei stained with DAPI (blue), scale bar: 50 μm. B–E Quantification of cellular immunofluorescence (n = 6 per group). *P < 0.05 vs. control. #P < 0.05 vs. Sup group. F Representative western blot images of COL1A1, COL3A1, MKX, SCXA, DCN, and TNMD. G, H. Sirius Red staining for collagen deposition (n = 6 per group). ***P < 0.001 vs. control group. ###P < 0.001 vs. Sup groupCC BY · PubMed Central
Fig. 3 Histological examination after application of HUMSC-Exos at injured tendons. A, B Representative H&E staining and Masson staining. C, D Histology score of tendons at 2 and 4 weeks after injury. HUMSC-Exo-treated tendons showed better tendon morphology and density than the sham and fibrin groups. Histological evaluation, the HUMSC-Exo group scores were lower than those of the sham group (n = 6 per group). Scale bar: 100 μm. W: wound region, T: normal region. The yellow dotted line indicates the boundary between the new tendon tissue and normal tissue after injury. ***P < 0.001
Fig. 3 Histological examination after application of HUMSC-Exos at injured tendons. A, B Representative H&E staining and Masson staining. C, D Histology score of tendons at 2 and 4 weeks after injury. HUMSC-Exo-treated tendons showed better tendon morphology and density than the sham and fibrin groups. Histological evaluation, the HUMSC-Exo group scores were lower than those of the sham group (n = 6 per group). Scale bar: 100 μm. W: wound region, T: normal region. The yellow dotted line indicates the boundary between the new tendon tissue and normal tissue after injury. ***P < 0.001CC BY · PubMed Central
Fig. 4 HUMSC-Exos improved histochemical and biomechanical performance in vivo. A–D Representative immunohistochemical staining and quantification of COL1A1, TNMD, and SCXA (n = 6 per group). Scale bar: 100 μm. Red arrow: tendon marker (COL1A1, TNMD, and SCXA) positive areas. ***P < 0.001. E–G Biomechanical analysis of ultimate tensile strength (N), stiffness (N/mm), and Young’s modulus (MPa) (n = 6 per group). *P < 0.05, **P < 0.01, ***P < 0.001
Fig. 4 HUMSC-Exos improved histochemical and biomechanical performance in vivo. A–D Representative immunohistochemical staining and quantification of COL1A1, TNMD, and SCXA (n = 6 per group). Scale bar: 100 μm. Red arrow: tendon marker (COL1A1, TNMD, and SCXA) positive areas. ***P < 0.001. E–G Biomechanical analysis of ultimate tensile strength (N), stiffness (N/mm), and Young’s modulus (MPa) (n = 6 per group). *P < 0.05, **P < 0.01, ***P < 0.001CC BY · PubMed Central
Fig. 5 HUMSC-Exos improved the performance of immunostaining of tendon regeneration in vivo. A Representative immunostaining staining of COL1A1. B Representative immunostaining staining of TNMD. C Quantification of COL1A1 staining. D Quantification of TNMD staining (n = 6 per group). Scale bar: 100 μm. ***P < 0.001
Fig. 5 HUMSC-Exos improved the performance of immunostaining of tendon regeneration in vivo. A Representative immunostaining staining of COL1A1. B Representative immunostaining staining of TNMD. C Quantification of COL1A1 staining. D Quantification of TNMD staining (n = 6 per group). Scale bar: 100 μm. ***P < 0.001CC BY · PubMed Central
Fig. 6 MiRNA sequencing analysis. A Heat map of miRNA sequencing (miRNA-seq) analysis of rat tendons treated with or without HUMSC-Exos (red: high expression, green: low expression, A1–A3 sham group, B1–B3 HUMSC-Exo group (n = 3 per group), and red arrow: rno-miR-29a-3p. B, C, D The expression of hsa-miR-29a-3p and rno-miR-29a-3p determined by Q-RT-PCR (n = 5 per group). ***P < 0.001. E KEGG analysis chart of miRNA-seq. F Representative western blot image of p-mTOR and mTOR
Fig. 6 MiRNA sequencing analysis. A Heat map of miRNA sequencing (miRNA-seq) analysis of rat tendons treated with or without HUMSC-Exos (red: high expression, green: low expression, A1–A3 sham group, B1–B3 HUMSC-Exo group (n = 3 per group), and red arrow: rno-miR-29a-3p. B, C, D The expression of hsa-miR-29a-3p and rno-miR-29a-3p determined by Q-RT-PCR (n = 5 per group). ***P < 0.001. E KEGG analysis chart of miRNA-seq. F Representative western blot image of p-mTOR and mTORCC BY · PubMed Central
Fig. 7 HUMSC-Exos activated PTEN/mTOR/TGF-β1 signaling to promote tendon repair by delivering miR-29a-3p. A Base sequence of hsa-miR-29a-3p and illustration of luciferase reporter gene containing the wild-type and mutant 3′UTR region of PTEN with binding sequence of hsa-miR-29a-3p. B Relative luciferase activity after transfection. C Representative western blot images of PTEN, TGF-β1, p-AKT, AKT, p-mTOR and mTOR. D–G Quantification of the relative gray level of the PTEN, TGF-β1 and relative ratio of p-AKT/AKT, p-mTOR/mTOR. H Representative western blot images of COL1A1, COL3A1, DCN, and SCXA. I–L Quantitative analysis of COL1A1, COL3A1, DCN, and SCXA (n = 3 per group). *P < 0.05, **P < 0.01, ***P < 0.001. ns not significant
Fig. 7 HUMSC-Exos activated PTEN/mTOR/TGF-β1 signaling to promote tendon repair by delivering miR-29a-3p. A Base sequence of hsa-miR-29a-3p and illustration of luciferase reporter gene containing the wild-type and mutant 3′UTR region of PTEN with binding sequence of hsa-miR-29a-3p. B Relative luciferase activity after transfection. C Representative western blot images of PTEN, TGF-β1, p-AKT, AKT, p-mTOR and mTOR. D–G Quantification of the relative gray level of the PTEN, TGF-β1 and relative ratio of p-AKT/AKT, p-mTOR/mTOR. H Representative western blot images of COL1A1, COL3A1, DCN, and SCXA. I–L Quantitative analysis of COL1A1, COL3A1, DCN, and SCXA (n = 3 per group). *P < 0.05, **P < 0.01, ***P < 0.001. ns not significantCC BY · PubMed Central
Fig. 8 Agomir-29a-Exo amplified gain effect on improving tendon healing. A Representative immunohistochemical staining of COL1A1, COL3A1, TNMD, and SCXA. Quantification of the B COL1A1, C COL3A1, D TNMD, and E SCXA staining (n = 6 per group, scale bar: 100 μm). Red arrow: tendon marker (COL1A1, COL3A1, TNMD, and SCXA) positive areas. ***P < 0.001. Biomechanical analysis of F ultimate tensile strength (N), G stiffness (N/mm), and H Young’s modulus (MPa) (n = 6 per group). *P < 0.05
Fig. 8 Agomir-29a-Exo amplified gain effect on improving tendon healing. A Representative immunohistochemical staining of COL1A1, COL3A1, TNMD, and SCXA. Quantification of the B COL1A1, C COL3A1, D TNMD, and E SCXA staining (n = 6 per group, scale bar: 100 μm). Red arrow: tendon marker (COL1A1, COL3A1, TNMD, and SCXA) positive areas. ***P < 0.001. Biomechanical analysis of F ultimate tensile strength (N), G stiffness (N/mm), and H Young’s modulus (MPa) (n = 6 per group). *P < 0.05CC BY · PubMed Central
Fig. 9 The underlying mechanism of HUMSC-Exos dependent tendon repair
Fig. 9 The underlying mechanism of HUMSC-Exos dependent tendon repairCC BY · PubMed Central

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Authors
Yao, Z., Li, J., Xiong, H., Cui, H., Ning, J., Wang, S., Ouyang, X., Qian, Y., & Fan, C.
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2021-06-05
Volume
19
Issue
1
ISSN
1477-3155
DOI
10.1186/s12951-021-00906-4
PMC
PMC8180131
Cited by
84
References
5
Language
en
Licence
Funders
National Natural Science Foundation of China (81830076, 82002290)

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CoChat. (2026). Citation check: MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling. https://app.cochat.ai/papers/10.1186/s12951-021-00906-4
The paper
Yao, Z., Li, J., Xiong, H., Cui, H., Ning, J., Wang, S., Ouyang, X., Qian, Y., & Fan, C. (2021). MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling. Journal of Nanobiotechnology. https://doi.org/10.1186/s12951-021-00906-4