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

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dc.contributor.authorGrzelak, C.A.
dc.contributor.authorMartelotto, L.G.
dc.contributor.authorSigglekow, N.D.
dc.contributor.authorPatkunanathan, B.
dc.contributor.authorAjami, K.
dc.contributor.authorCalabro, S.R.
dc.contributor.authorDwyer, B.J.
dc.contributor.authorTirnitz-Parker, J.E.E.
dc.contributor.authorWatkins, D.N.
dc.contributor.authorWarner, F.J.
dc.contributor.authorShackel, N.A.
dc.contributor.authorMcCaughan, G.W.
dc.date.issued2014
dc.description.abstractBackground & 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 SMOdependent/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.
dc.description.statementofresponsibilityCandice Alexandra Grzelak, Luciano Gastón Martelotto, Nicholas David Sigglekow, Bramilla Patkunanathan, Katerina Ajami, Sarah Ruth Calabro, Benjamin James Dwyer, Janina Elke Eleonore Tirnitz-Parker, D. Neil Watkins, Fiona Jane Warner, Nicholas Adam Shackel, Geoffrey William McCaughan
dc.identifier.citationJournal of Hepatology, 2014; 60(1):143-151
dc.identifier.doi10.1016/j.jhep.2013.08.012
dc.identifier.issn0168-8278
dc.identifier.issn1600-0641
dc.identifier.orcidMartelotto, L.G. [0000-0002-9625-1183]
dc.identifier.urihttps://hdl.handle.net/2440/134522
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/632701
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/571408
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/546098
dc.rights© 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.jhep.2013.08.012
dc.subjectHedgehog signalling pathway; Primary cilia; Liver progenitor cells; Non-canonical cell signalling; GLI; Smoothened; Thioacetamide
dc.subject.meshLiver
dc.subject.meshCilia
dc.subject.meshAnimals
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice
dc.subject.meshChronic Disease
dc.subject.meshThioacetamide
dc.subject.meshReceptors, G-Protein-Coupled
dc.subject.meshNuclear Proteins
dc.subject.meshSignal Transduction
dc.subject.meshMale
dc.subject.meshKruppel-Like Transcription Factors
dc.subject.meshHedgehog Proteins
dc.subject.meshEpithelial-Mesenchymal Transition
dc.subject.meshChemical and Drug Induced Liver Injury
dc.subject.meshZinc Finger Protein GLI1
dc.subject.meshSmoothened Receptor
dc.subject.meshZinc Finger Protein Gli2
dc.titleThe intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury
dc.typeJournal article
pubs.publication-statusPublished

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