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Extracellular vesicles derived from bone marrow mesenchymal stem cells ameliorate chronic liver damage via microRNA-136-5p

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Abstract

Chronic liver damage (CLD) encompasses a spectrum of conditions and poses a significant global health challenge, affecting millions of individuals. Currently, there is a deficiency of clinically validated therapeutics with minimal side effects. Emerging evidence underscores the significant potential of extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) as a promising therapeutic method for CLD. This study aimed to evaluate the influence of BMSC-EVs containing microRNA-136-5p (BMSC-EVs-miR-136-5p) on macrophage polarization during chronic liver injury and elucidate the mechanisms associated with the GNAS/PI3K/ERK/STAT3 axis. Surface markers of BMSCs were detected via Immunofluorescent Staining. Subsequently, EVs were harvested from the BMSC culture medium. In vivo fluorescence imaging was employed to locate the BMSC-EVs. Additionally, fluorescence microscopy was used to visualize the uptake of DIR-labeled BMSC-EVs by RAW264.7 cells. Various methods were employed to assess the impact of BMSC-EVs on the expression levels of inflammatory factors (IL-1β, IL-6, IL-10, and TNF-α), M1/M2 macrophage markers (iNOS and Arg-1), and members of inflammation-related signaling pathways (GNAS, PI3K, ERK, and STAT3) in RAW264.7 cells co-cultured with BMSC-EVs. Loss-of-function approaches targeting miR-136-5p in RAW264.7 cells were subsequently utilized to validate the role of BMSC-EVs-miR-136-5p. The Luciferase Reporter Assay indicates that GNAS was identified to be a target of miR-136-5p, and miR-136-5p demonstrating increased within BMSC-EVs compared to Raw264.7-EVs. BMSC-EVs-miR-136-5p mitigated CCl4-induced liver inflammation and improved liver function by Suppressing the GNAS/STAT3 Signaling. Notably, miR-136-5p suppressed lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. BMSC-EVs-miR-136-5p alleviates CLD by activating M2 polarization through the GNAS-mediated PI3K/ERK/STAT3 axis. Accordingly, the members of this axis may serve as therapeutic targets.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank the reviewers and also the authors of all references.

Funding

This work was supported by grants from the National Natural Science Foundation of China (to Wenlan Liu) (Grant No. 81573879) and the Natural Science Foundation of Beijing (to Wenlan Liu) (Grant No. 7182021).

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Authors and Affiliations

  1. School of Traditional Chinese Medicine, Capital Medical University, Beijing, China

    Xiaodan Jiang, Zhejun Liu, Ruifang Nie, Niancong Che & Wenlan Liu

  2. School of Basic Medical Sciences, Capital Medical University, Beijing, China

    Hongjie You, Zuoqing Tang, Yun Ma & Zheng Yang

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  1. Xiaodan Jiang
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Contributions

Xiaodan Jiang as principal author was responsible for processing experiments, collecting, and analyzing data, finally independently wrote this manuscript. Wenlan Liu performed conception and design of study and reviewed manuscript, and acted as corresponding author. Zhejun Liu and Ruifang Nie contributed to complete experiments. Hongjie You, Zuoqing Tang, Yun Ma, Zheng Yang, and Niancong Che contributed to data interpretation.

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Correspondence to Wenlan Liu.

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Jiang, X., Liu, Z., You, H. et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells ameliorate chronic liver damage via microRNA-136-5p. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04993-3

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