TGF-β in progression of liver diseaseReport as inadecuate




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Cell and Tissue Research

, Volume 347, Issue 1, pp 245–256

First Online: 19 October 2011Received: 18 July 2011Accepted: 12 September 2011

Abstract

Transforming growth factor-β TGF-β is a central regulator in chronic liver disease contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver-damage-induced levels of active TGF-β enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Being recognised as a major profibrogenic cytokine, the targeting of the TGF-β signalling pathway has been explored with respect to the inhibition of liver disease progression. Whereas interference with TGF-β signalling in various short-term animal models has provided promising results, liver disease progression in humans is a process of decades with different phases in which TGF-β or its targeting might have both beneficial and adverse outcomes. Based on recent literature, we summarise the cell-type-directed double-edged role of TGF-β in various liver disease stages. We emphasise that, in order to achieve therapeutic effects, we need to target TGF-β signalling in the right cell type at the right time.

KeywordsTGF-β Epithelial-to-mesenchymal transition Fibrosis Hepatic stellate cell Hepatocellular carcinoma Inflammation Liver disease AbbreviationsALKActivin receptor-like kinase

BDECBile duct epithelial cells

CCl4Carbon tetrachloride

CDKCyclin-dependent kinase

CLDChronic liver disease

CSCCancer stem cells

CTGFConnective tissue growth factor

EGFREpidermal growth factor receptor

EMTEpithelial to mesenchymal transition

ECMExtracellular matrix

FSP1Fibroblast-specific protein-1

GFPGreen fluorescent protein

HBVHepatitis B virus

HCCHepatocellular carcinoma

HCVHepatitis C virus

HPCHepatic progenitor cells

HSCHepatic stellate cells

IFNInterferon

JNKc-Jun amino terminal kinase

NASHNon-alcoholic steatohepatitis

PHxPartial hepatectomy

ROSReactive oxygen species

SMASmooth muscle actin

TGF-βTransforming growth factor-β

TβRTGF-β receptor

YFPYellow fluorescent protein

Our studies of the role of TGF-β in fibrosis are supported by the Netherlands Institute for Regenerative Medicine NIRM, the Netherlands Organisation for Scientific Research NWO-MW, the Centre for Biomedical Genetics PtD, the German Research Foundation with the programs SFB TRR77 Liver Cancer TP A6 and Do373-8-1 and BMBF grants The Virtual Liver and Cell Therapy in Liver Regeneration.

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Author: Steven Dooley - Peter ten Dijke

Source: https://link.springer.com/



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