Abstract
The Wnt system is highly complex and is comprised of canonical and non-canonical pathways leading to the activation of gene expression. Our aim was to examine changes in the expression of Wnt ligands and regulators during hepatic stellate cell (HSC) transdifferentiation and assess the relative contributions of the canonical and non-canonical Wnt pathways in fibrogenic activated HSC. The expression profile of Wnt ligands and regulators in HSC was not supportive for a major role for β-catenin-dependent canonical Wnt signalling, this verified by inability to induce Topflash reporter activity in HSC even when expressing a constitutive active β-catenin. We detected expression of Wnt5a in activated HSC which can signal via non-canonical mechanisms and showed evidence for non-canonical signalling in these cells involving phosphorylation of Dvl2 and pJNK. Stimulation of HSC or Kupffer cells with Wnt5a regulated HSC apoptosis and expression of TGF-β1 and MCP1 respectively. We were unable to confirm a role for β-catenin-dependent canonical Wnt in HSC and instead propose autocrine and paracrine functions for Wnts expressed by activated HSC via non-canonical pathways. The data warrant detailed investigation of Wnt5a in liver fibrosis.
Highlights
Hepatic stellate cells (HSC) are widely recognised as the major cellular origin of activated profibrogenic myofibroblasts in chronic liver disease, irrespective of disease aetiology
Activated phenotype with maximal expression observed between days 6 and 10 when the cells have matured to a myofibroblastic state (Fig 1C) Western blotting for alpha smooth muscle actin (α-SMA) and TGFβ confirmed that 7-day cultured rat HSC were in an activated state while blotting for Wnt5a confirmed induction of this Wnt ligand at the protein level (Fig 1D)
The Wnt signalling system has been the subject of considerable attention in HSCs and liver fibrosis with recent reports suggesting functions in HSC transdifferentiation, proliferation, apoptosis, control of fibrogenic gene expression and regulatory interactions of activated HSC (aHSC) with other liver cell types and physiological responses such as hepatocellular regeneration[11,13,14]
Summary
Hepatic stellate cells (HSC) are widely recognised as the major cellular origin of activated profibrogenic myofibroblasts in chronic liver disease, irrespective of disease aetiology. In response to liver damage HSC undergo an epigenetically-regulated transdifferentiation to adopt a myofibroblast-like phenotype characterised by proliferation, contractile ability and the secretion of vast amounts of fibril-forming extracellular matrix (ECM) proteins[1]. The persistence of these so-called activated HSC (aHSC) leads to the net deposition of ECM and the progressive remodelling of liver tissue towards a fibrotic state. Non-Canonical Wnt Predominates in Activated Hepatic Stellate Cells of chronic liver disease to cirrhosis. Key to exploiting the aHSC for the development of antifibrotic strategies is a deep understanding of the regulatory cell signalling processes that dictate their fibrogenic activities
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