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The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury

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Authors
Grzelak, C.
Martelotto, L.
Sigglekow, N.
Patkunanathan, B.
Ajami, K.
Calabro, S.
Dwyer, Benjamin
Tirnitz-Parker, Janina
Watkins, D.
Warner, F.
Shackel, N.
McCaughan, G.
Date
2014
Type
Journal Article

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Grzelak, Candice Alexandra and Martelotto, Luciano Gaston and Sigglekow, Nicholas David and Patkunanathan, Bramilla and Ajami, Katerina and Calabro, Sarah Ruth and Dwyer, Benjamin James and Tirnitz-Parker, Janina Elke Eleonore and Watkins, D. Neil and Warner, Fiona Jane and Shackel, Nicholas Adam and McCaughan, Geoffrey William. 2014. The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury. Journal of Hepatology. 60 (1): pp. 143-151.
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Journal of Hepatology
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This is the author’s version of a work that was accepted for publication in the Journal of Hepatology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in the Journal of Hepatology, Volume 60, Issue 1, January 2014, Pages 143–151. http://doi.org/10.1016/j.jhep.2013.08.012

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Abstract

Background & Aims: In vertebrates, canonical Hedgehog (Hh) pathway activation requires Smoothened (SMO) translocation to the primary cilium (Pc), followed by a GLI-mediated transcriptional response. In addition, a similar gene regulation occurs in response to growth factors/cytokines, although independently of SMO signalling. The Hh pathway plays a critical role in liver fibrosis/regeneration; however, the mechanism of activation in chronic liver injury is poorly understood. This study aimed to characterise Hh pathway activation upon thioacetamide (TAA)- induced chronic liver injury in vivo by defining Hh-responsive cells, namely cells harbouring Pc and Pc-localised SMO. Methods: C57BL/6 mice (wild-type or Ptc1+/_) were TAA-treated. Liver injury and Hh ligand/pathway mRNA and protein expression were assessed in vivo. SMO/GLI manipulation and SMO dependent/ independent activation of GLI-mediated transcriptional response in Pc-positive (Pc+) cells were studied in vitro. Results: In vivo, Hh activation was progressively induced following TAA. At the epithelial-mesenchymal interface, injured hepatocytes produced Hh ligands. Progenitors, myofibroblasts, leukocytes and hepatocytes were GLI2+. Pc+ cells increased following TAA, but only EpCAM+/GLI2+ progenitors were Pc+/SMO+. In vitro, SMO knockdown/hGli3-R overexpression reduced proliferation/viability in Pc+ progenitors, whilst increased proliferation occurred with hGli1 overexpression. HGF induced GLI transcriptional activity independently of Pc/SMO. Ptc1+/_ mice exhibited increased progenitor, myofibroblast and fibrosis responses. Conclusions: In chronic liver injury, Pc+ progenitors receive Hh ligand signals and process it through Pc/SMO-dependent activation of GLI-mediated transcriptional response. Pc/SMO-independent GLI activation likely occurs in Pc_/GLI2+ cells. Increased fibrosis in Hh gain-of-function mice likely occurs by primary progenitor expansion/proliferation and secondary fibrotic myofibroblast expansion, in close contact with progenitors.