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. 2025 May;480(5):2903-2921.
doi: 10.1007/s11010-024-05152-4. Epub 2024 Nov 8.

Extracellular vesicles derived from bone marrow mesenchymal stem cells ameliorate liver fibrosis via micro-7045-5p

Zhejun Liu  1 , Xiaodan Jiang  1 , Hongjie You  2 , Zuoqing Tang  2 , Yun Ma  2 , Niancong Che  1 , Wenlan Liu  3   4 , Chongyang Ma  5   6
Affiliations

Extracellular vesicles derived from bone marrow mesenchymal stem cells ameliorate liver fibrosis via micro-7045-5p

Zhejun Liu et al. Mol Cell Biochem. 2025 May.

Abstract

Introduction: Liver fibrosis is a crucial pathological factor in the persistence and progression of chronic liver disease. Increasing evidence has demonstrated the significant potential of extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) in the clinical treatment of liver fibrosis. This study aimed to mechanistically investigate the impact of BMSC-derived EVs (BMSC-EVs) containing miR-7045-5p on the autophagy of activated hepatic stellate cells (HSCs) during liver fibrosis.

Method: BMSCs were isolated from the bilateral femurs and tibiae of mice. Their identity was confirmed via immunofluorescence staining for the BMSC marker CD44. EVs were harvested from BMSC culture medium at passages 3-5 and then DiR-labeled. Labeled BMSC-EVs were co-cultured with the HSC-T6 cell line to determine their uptake and sub-cellular localization in HSCs. Various methods, such as western blotting, qRT-PCR, and ELISA, were employed to assess the effects of BMSC-EVs on the fibrotic activation (marked by COL1-A1 and α-SMA expression) and autophagy (p62, Atg16L1, Beclin-1, and LC3 expression) of HSC-T6 cells. Additionally, the BMSC-EV-induced changes in autophagy-related signaling pathways (PI3K, AKT, and mTOR pathways) in these cells were evaluated. Finally, the gene-chip detection technology was utilized to predict the involvement of BMSC-EV-derived miRNAs (BMSC-EV-miRs) in the observed effects, with a focus on miR-7045-5p, and our findings were validated in HSCs transfected with a miR-7045-5p mimic.

Result: The gene-chip detection results indicated that miR-7045-5p was enriched in BMSC-EVs compared with BMSCs and targeted Akt. In the CCl4-induced mouse model of liver fibrosis, BMSC-EV-miR-7045-5p ameliorated the fibrosis and enhanced liver function by suppressing the PI3K/Akt/mTOR signaling pathway. Additionally, miR-7045-5p inhibited TGF-β1-induced fibrotic activation of HSC-T6 cells.

Conclusion: BMSC-EVs promote autophagy in HSC-T6 cells and alleviate liver fibrosis by inhibiting the PI3K/Akt/mTOR signaling pathway at least in part by delivering anti-fibrotic miRNAs, such as miR-7045-5p.

Keywords: Autophagy; Bone marrow mesenchymal stem cells; Extracellular vesicles; Liver fibrosis; MicroRNA-7045-5p.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval and consent to participate: Not applicable. Consent for publication: Not applicable. Institutional review board statement: All the experimental animal procedures were performed in strict accordance with the guidelines of the Ethics Committee of Capital Medical University.

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