Tags

Type your tag names separated by a space and hit enter

The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury.
J Hepatol 2014; 60(1):143-51JH

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.

Authors+Show Affiliations

Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia.Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, VIC, Australia; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia.Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia.Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia.Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia.School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, VIC, Australia.Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia.Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia; A. W. Morrow Gastroenterology and Liver Centre, R.P.A.H., Camperdown, NSW, Australia; Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia; A. W. Morrow Gastroenterology and Liver Centre, R.P.A.H., Camperdown, NSW, Australia; Faculty of Medicine, University of Sydney, Sydney, NSW, Australia. Electronic address: g.mccaughan@centenary.org.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23978713

Citation

Grzelak, Candice Alexandra, et al. "The Intrahepatic Signalling Niche of Hedgehog Is Defined By Primary Cilia Positive Cells During Chronic Liver Injury." Journal of Hepatology, vol. 60, no. 1, 2014, pp. 143-51.
Grzelak CA, Martelotto LG, Sigglekow ND, et al. The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury. J Hepatol. 2014;60(1):143-51.
Grzelak, C. A., Martelotto, L. G., Sigglekow, N. D., Patkunanathan, B., Ajami, K., Calabro, S. R., ... McCaughan, G. W. (2014). The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury. Journal of Hepatology, 60(1), pp. 143-51. doi:10.1016/j.jhep.2013.08.012.
Grzelak CA, et al. The Intrahepatic Signalling Niche of Hedgehog Is Defined By Primary Cilia Positive Cells During Chronic Liver Injury. J Hepatol. 2014;60(1):143-51. PubMed PMID: 23978713.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury. AU - Grzelak,Candice Alexandra, AU - Martelotto,Luciano Gastón, AU - Sigglekow,Nicholas David, AU - Patkunanathan,Bramilla, AU - Ajami,Katerina, AU - Calabro,Sarah Ruth, AU - Dwyer,Benjamin James, AU - Tirnitz-Parker,Janina Elke Eleonore, AU - Watkins,D Neil, AU - Warner,Fiona Jane, AU - Shackel,Nicholas Adam, AU - McCaughan,Geoffrey William, Y1 - 2013/08/23/ PY - 2013/04/09/received PY - 2013/07/02/revised PY - 2013/08/05/accepted PY - 2013/8/28/entrez PY - 2013/8/28/pubmed PY - 2014/9/27/medline KW - ALD KW - ALT KW - CK KW - DHH KW - Desert Hedgehog KW - EGF KW - EMT KW - EpCAM KW - GLI KW - GLI cleaved repressor KW - GLI full-length activator KW - GLI-A KW - GLI-Kruppel family of transcription factors KW - GLI-R KW - HGF KW - HSC KW - Hedgehog KW - Hedgehog signalling pathway KW - Hh KW - IHH KW - Indian Hedgehog KW - LPC KW - Liver progenitor cells KW - MCDE KW - N-Hh KW - N-terminal Hedgehog signalling peptide KW - NT2 KW - Non-canonical cell signalling KW - PTCH1 KW - Patched 1 KW - Pc KW - Primary cilia KW - Ptc1(+/−) KW - Ptc1-lacZ reporter KW - SHH KW - SMO KW - Smoothened KW - Sonic Hedgehog KW - TAA KW - Thioacetamide KW - alanine aminotransferase KW - alcoholic liver disease KW - cytokeratin KW - epidermal growth factor KW - epithelial cell adhesion molecule KW - epithelial-to-mesenchymal transition KW - hepatic stellate cell KW - hepatocyte growth factor KW - liver progenitor cell KW - methionine choline-deficient diet+ethionine KW - non-targeting control KW - primary cilia KW - thioacetamide KW - α-SMA KW - α-smooth muscle actin SP - 143 EP - 51 JF - Journal of hepatology JO - J. Hepatol. VL - 60 IS - 1 N2 - 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. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/23978713/The_intrahepatic_signalling_niche_of_hedgehog_is_defined_by_primary_cilia_positive_cells_during_chronic_liver_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(13)00606-5 DB - PRIME DP - Unbound Medicine ER -