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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Akcora, Busra Ozturk¹  Storm, Gert^1,2  Bansal, Ruchi¹ 

[1] Univ Twente, MIRA Inst Biomed Technol & Tech Med, Dept Biomat Sci & Technol, Targeted Therapeut,Fac Sci & Technol, Enschede, Netherlands

[2] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, Fac Sci, Utrecht, Netherlands

关键词: Wnt signaling pathway;    Myofibroblasts;    CXCL12;    Liver fibrosis;    Intrahepatic inflammation;    Angiogenesis;   

DOI  :  10.1016/j.bbadis.2017.12.001

来源: Elsevier

【 摘 要 】

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 beta-catenin/CBP inhibitor ICG001 was examined in-vitro in TGF beta-activated 3T3, LX2, primary human HSCs, and in-vivo in CCI4-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.

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