EphB2 receptor tyrosine kinase promotes hepatic fibrogenesis in mice via activation of hepatic stellate cells

• Type of Material: Article
• Authors: Patrice Mimche Nsangou, Emory University; Choon-Myung Lee, Emory University; Sylvie M. Mimche, Emory University; Manoj Thapa, Emory University; Arash Grakoui, Emory University; Mark Henkemeyer, University of Texas Southwestern Medical Center; Tracey J. Lamb, University of Utah
• Language: English
• Date: 2018-02-07
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-018-20926-9
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 8
• Issue: 1
• Start Page: 2532
• End Page: 2532
• Grant/Funding Information: Part of this study was funded by the National Institute for Neurological Disorders and Strokes grant to TJL (1R21NS085382-01A1).; M.T. is supported by National Institute of Diabetes, and Digestive and Kidney Diseases (NIDDK) Mentored Career Development Award (K01DK109025).; Microscopy equipment was obtained using a NCRR Shared Equipment Grant #1S10RR024761-01.
• Keywords: FIBROTIC LIVER; EPHRIN; PATHWAY; ORIGIN; CANCER; Multidisciplinary Sciences; Science & Technology - Other Topics; Science & Technology; MYOFIBROBLASTS; MESENCHYMAL TRANSITION; EXPRESSION; TGF-BETA; LIVER FIBROSIS
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology; Health Sciences, Pharmacology

Abstract

Hepatic fibrosis is the result of an excessive wound-healing response subsequent to chronic liver injury. A feature of liver fibrogenesis is the secretion and deposition of extracellular matrix proteins by activated hepatic stellate cells (HSCs). Here we report that upregulation of EphB2 is a prominent feature of two mouse models of hepatic fibrosis and also observed in humans with liver cirrhosis. EphB2 is upregulated and activated in mouse HSCs following chronic carbon tetrachloride (CCl 4 ) exposure. Moreover, we show that EphB2 deficiency attenuates liver fibrosis and inflammation and this is correlated with an overall reduction in pro-fibrotic markers, inflammatory chemokines and cytokines. In an in vitro system of HSCs activation we observed an impaired proliferation and sub-optimal differentiation into fibrogenic myofibroblasts of HSCs isolated from EphB2-/- mice compared to HSCs isolated from wild type mice. This supports the hypothesis that EphB2 promotes liver fibrosis partly via activation of HSCs. Cellular apoptosis which is generally observed during the regression of liver fibrogenesis was increased in liver specimens of CCl 4 -treated EphB2-/- mice compared to littermate controls. This data is suggestive of an active repair/regeneration system in the absence of EphB2. Altogether, our data validate this novel pro-fibrotic function of EphB2 receptor tyrosine kinase.