Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12.

Abstract

Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl4-induced acute liver injury mouse model. Fibroblasts-conditioned medium studies were performed to assess the Wnt-regulated paracrine factors involved in crosstalk between HSCs-macrophages and HSCs-endothelial cells. Canonical Wnt signaling pathway components were significantly up-regulated in-vitro and in-vivo. In-vitro, ICG-001 significantly inhibited fibrotic parameters, 3D-collagen contractility and wound healing. Conditioned medium induced fibroblasts-mediated macrophage and endothelial cells activation was significantly inhibited by ICG-001. In-vivo, ICG-001 significantly attenuated collagen accumulation and HSC activation. Interestingly, ICG-001 drastically inhibited macrophage infiltration, intrahepatic inflammation and angiogenesis. We further analyzed the paracrine factors involved in Wnt-mediated effects and found CXCL12 was significantly suppressed both in-vitro and in-vivo following Wnt inhibition. Wnt-regulated CXCL12 secretion from activated HSCs potentiated macrophage infiltration and activation, and angiogenesis. Pharmacological inhibition of canonical Wnt signaling pathway via suppression of stromal CXCL12 suggests a potential therapeutic approach targeting activated HSCs in liver fibrosis.

• Authors: Büsra Öztürk Akcora, Gert Storm, Ruchi Bansal
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1864 Issue 3 Pg. 804-818 (Mar 2018) ISSN: 0925-4439 [Print] Netherlands
• PMID: 29217140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• ICG 001
• Pyrimidinones
• beta Catenin
• CREB-Binding Protein
• CREBBP protein, human

Topics

• 3T3 Cells
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology, therapeutic use)
• CREB-Binding Protein (antagonists & inhibitors)
• Cells, Cultured
• Hepatic Stellate Cells (drug effects, metabolism)
• Humans
• Liver (cytology, drug effects, metabolism)
• Liver Cirrhosis (drug therapy, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Pyrimidinones (pharmacology, therapeutic use)
• Stromal Cells (drug effects, metabolism)
• Wnt Signaling Pathway (drug effects)
• beta Catenin (antagonists & inhibitors)