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Liver-derived extracellular vesicles from patients with hepatitis B virus-related acute-on-chronic liver failure impair hepatic regeneration by inhibiting on FGFR2 signaling via miR-218-5p

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Abstract

Background

Impaired liver regeneration in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients is closely related to prognosis; however, the mechanisms are not yet defined. Liver-derived extracellular vesicles (EVs) may be involved in the dysregulation of liver regeneration. Clarifying the underlying mechanisms will improve the treatments for HBV-ACLF.

Methods

EVs were isolated by ultracentrifugation from liver tissues of HBV-ACLF patients (ACLF_EVs) after liver transplantation, and their function was investigated in acute liver injury (ALI) mice and AML12 cells. Differentially expressed miRNAs (DE-miRNAs) were screened by deep miRNA sequencing. The lipid nanoparticle (LNP) system was applied as a carrier for the targeted delivery of miRNA inhibitors to improve its effect on liver regeneration.

Results

ACLF_EVs inhibited hepatocyte proliferation and liver regeneration, with a critical role of miR-218-5p. Mechanistically, ACLF_EVs fused directly with target hepatocytes and transferred miR-218-5p into hepatocytes, acting by suppressing FGFR2 mRNA and inhibiting the activation of ERK1/2 signaling pathway. Reducing the level of miR-218-5p expression in the liver of ACLF mice partially restored liver regeneration ability.

Conclusion

The current data reveal the mechanism underlying impaired liver regeneration in HBV-ACLF that promotes the discovery of new therapeutic approaches.

Graphical abstract

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Data availability

Sequencing data generated in this study has been deposited at the National Omics Data Encyclopedia (NODE) under the accession code OEP004077 (https://www.biosino.org/node/project/detail/OEP004077).

Abbreviations

CCl4 :

Carbon tetrachloride

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

LDH:

Lactate dehydrogenase

TBIL:

Total bilirubin

BUN:

Blood urea nitrogen

ACLF:

Acute-on-chronic liver failure

HC:

Healthy control

CI:

Chronic inflammation

EVs:

Extracellular vesicles

ACLF_EVs:

Liver-derived extracellular vesicles from ACLF

HC_EVs:

Liver-derived extracellular vesicles from healthy control

H&E staining:

Hematoxylin–eosin staining

PCNA:

Proliferating cell nuclear antigen

CCK-8:

Cell Counting Kit-8

DAPI:

4′,6-Diamidino-2-phenylindole

EdU:

5-Ethynyl-2′-deoxyuridine

LC:

Liver cirrhosis

LC_EVs:

Liver-derived extracellular vesicles from LC

DE-miRNAs:

Differentially expressed miRNAs

KEGG:

Kyoto Encyclopedia of Genes and Genomes

GO:

Gene ontology

FGFR2:

Fibroblast Growth Factor Receptor 2

ALB:

Albumin

miR_veh:

miR-vehicle

miR_inh:

miR-inhibitor

miR_ago:

miR-agomir

miR_ant:

miR-antagomir

LNP:

Lipid nanoparticle

NPCs:

Nonparenchymal cells

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Acknowledgements

The authors acknowledge the patients, study investigators, and coordinators for their contributions in this study.

Funding

This study was supported by the National Natural Science Foundation of China (82170646 to Hualian Hang), “Key Project” of Shanghai Jiao Tong University Medical-Industry Intersection (YG2021ZD10 to Hualian Hang), Clinical Research Innovation Cultivation Fund of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (RJPY-DZX-006 to Hualian Hang).

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Author notes

  1. Senquan Zhang, Jie Yu, Keqiang Rao and Jie Cao have contributed equally to the research.

Authors and Affiliations

  1. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Senquan Zhang, Keqiang Rao, Jie Cao, Lijie Ma, Yeping Yu, Zhe Li, Zhaokai Zeng, Yongbing Qian, Mo Chen & Hualian Hang

  2. Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Jie Yu

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Contributions

All authors contributed to the study conception and design. SZ, JY and KR designed research; SZ, JY and KR and JC performed research; LM, YY, ZL and ZZ carried data analysis; YQ, MC and HH supervised research; SZ, JY and KR wrote the paper. All authors approved the manuscript.

Corresponding authors

Correspondence to Yongbing Qian, Mo Chen or Hualian Hang.

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Conflict of interest

Senquan Zhang, Jie Yu, Keqiang Rao, Jie Cao, Lijie Ma, Yeping Yu, Zhe Li, Zhaokai Zeng, Yongbing Qian, Mo Chen, Hualian Hang have no relevant financial or non-financial interests to disclose.

Ethics approval and consent to participate

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Ethics Committee of Renji Hospital of Shanghai Jiao Tong University School of Medicine, China) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study.

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Zhang, S., Yu, J., Rao, K. et al. Liver-derived extracellular vesicles from patients with hepatitis B virus-related acute-on-chronic liver failure impair hepatic regeneration by inhibiting on FGFR2 signaling via miR-218-5p. Hepatol Int 17, 833–849 (2023). https://doi.org/10.1007/s12072-023-10513-0

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