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

Xiaodan Jiang; Zhejun Liu; Hongjie You; Zuoqing Tang; Yun Ma; Ruifang Nie; Zheng Yang; Niancong Che; Wenlan Liu

doi:10.1007/s11010-024-04993-3

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

Mol Cell Biochem. 2024 Apr 23. doi: 10.1007/s11010-024-04993-3. Online ahead of print.

Authors

Xiaodan Jiang¹, Zhejun Liu¹, Hongjie You², Zuoqing Tang², Yun Ma², Ruifang Nie¹, Zheng Yang², Niancong Che¹, Wenlan Liu³

Affiliations

¹ School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
² School of Basic Medical Sciences, Capital Medical University, Beijing, China.
³ School of Traditional Chinese Medicine, Capital Medical University, Beijing, China. Wenlanliu1900@126.com.

PMID: 38652214
DOI: 10.1007/s11010-024-04993-3

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.

Keywords: Bone marrow mesenchymal stem cells (BMSC); Chronic liver damage (CLD); Extracellular vesicles (EV); Macrophage polarization; MicroRNA-136-5p.

Abstract

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