Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12
| Autor: | Akcora, Büsra Öztürk, Storm, Gert, Bansal, Ruchi, Afd Pharmaceutics, Pharmaceutics |
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| Přispěvatelé: | TechMed Centre, Biomaterials Science and Technology, Afd Pharmaceutics, Pharmaceutics |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Stromal Cells/drug effects Liver Cirrhosis Male Liver cytology Angiogenesis Heterocyclic/pharmacology Inbred C57BL Mice Myofibroblasts Cells Cultured beta Catenin Cultured Pyrimidinones/pharmacology Chemistry Wnt signaling pathway beta Catenin/antagonists & inhibitors Intrahepatic inflammation 3T3 Cells CXCL12 CREB-Binding Protein Cell biology Liver Molecular Medicine Stromal cell Cells Liver fibrosis Liver/cytology Hepatic Stellate Cells/drug effects Pyrimidinones 03 medical and health sciences Paracrine signalling Bridged Bicyclo Compounds Wnt Signaling Pathway/drug effects Hepatic Stellate Cells Animals Humans Molecular Biology Liver Cirrhosis/drug therapy Bridged Bicyclo Compounds Heterocyclic/pharmacology Bridged Bicyclo Compounds Heterocyclic Mice Inbred C57BL 030104 developmental biology Catenin Hepatic stellate cell CREB-Binding Protein/antagonists & inhibitors Stromal Cells Wound healing |
| Zdroj: | Biochimica et biophysica acta. Molecular basis of disease, 1864(3), 804-818. Elsevier Biochimica et Biophysica Acta. Molecular Basis of Disease, 1864(3), 804. Elsevier |
| ISSN: | 0925-4439 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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