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  2. Hepatocyte-derived exosomes deliver H2AFJ to hepatic stellate cells and promote liver fibrosis via the MAPK/STMN1 axis activation

Hepatocyte-derived exosomes deliver H2AFJ to hepatic stellate cells and promote liver fibrosis via the MAPK/STMN1 axis activation

  • Int Immunopharmacol. 2023 Jan 4;115:109605. doi: 10.1016/j.intimp.2022.109605.
Bin Liu 1 Jinchao Wang 2 Guangchuan Wang 3 Wanli Jiang 4 Zhen Li 3 Yongjun Shi 3 Junyong Zhang 3 Qingshan Pei 3 Guangjun Huang 3 Lifen Wang 3 Shengqiang Zhao 3 Lei Wu 3 Mingyan Zhang 3 Wenwen Wang 3 Xiao Li 3 Tong Mou 3 Chunqing Zhang 3 Qian Ding 5
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China.
  • 2 Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China.
  • 3 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China.
  • 4 First Clinical School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, PR China.
  • 5 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, PR China. Electronic address: dq224@163.com.
Abstract

Hepatic stellate cells (HSCs) activate and acquire proliferative features in response to liver injury. However, mechanisms involved in the activation of fibrotic HSCs remain uncharacterized. This study aims at elaborating the mechanistic basis by which exosomal H2AFJ derived from hepatocytes might affect the activation of HSCs and liver fibrosis. Bioinformatics analysis based on transcriptomic RNA-seq data was used to screen out the downstream regulatory genes and pathways of H2AFJ. Mouse hepatocytes AML-12 cells were stimulated with CCl4 to mimic an in vitro microenvironment of liver fibrosis, from which exosomes were isolated. Next, HSCs were co-cultured with hepatocyte-derived exosomes followed by detection of HSC migration and invasion in the presence of manipulated H2AFJ and STMN1 expression and MAPK pathway inhibitor. It was found that H2AFJ was highly expressed in hepatocyte-derived exosomes after CCl4 stimulation. Hepatocyte-derived exosomal H2AFJ promoted HSC migration and invasion. H2AFJ upregulated c-jun-mediated STMN1 by activating the MAPK signaling pathway. Furthermore, in vivo experiments verified that silencing of H2AFJ attenuated liver fibrosis in mice, while restoration of STMN1 negated its effect. Collectively, hepatocyte-derived exosomal H2AFJ aggravated liver fibrosis by activating the MAPK/STMN1 signaling pathway. This study provides a potential therapeutic target for alleviating liver fibrosis.

Keywords

Exosomes; H2AFJ; Hepatic stellate cells; Hepatocytes; Liver fibrosis; MAPK; STMN1.

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