Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo

Rebecca Lim; Belinda Knight; Keyur Patel; John G. McHutchison; George C. Yeoh; John K. Olynyk

doi:10.1002/hep.21170

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Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo

Journal article

Open access

Peer reviewed

Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo

Rebecca Lim, Belinda Knight, Keyur Patel, John G. McHutchison, George C. Yeoh and John K. Olynyk

Hepatology, Vol.43(5), pp.1074-1083

2006

DOI: https://doi.org/10.1002/hep.21170

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Abstract

Hepatic progenitor cells (called oval cells in rodents) proliferate during chronic liver injury. They have been suggested as targets of malignant transformation in chronic liver diseases, including chronic hepatitis C. Interferon alpha therapy reduces the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C regardless of viral clearance. The aim of this study was to determine whether interferon alpha could reduce the risk of HCC by modifying preneoplastic events in the hepatic progenitor cell population. Pre- and post-treatment liver biopsies were evaluated for changes in the hepatic progenitor cell population in 16 patients with non-responding chronic hepatitis C. Interferon alpha–based treatment significantly reduced the numbers of c-kit–positive hepatic progenitor cells by 50%. To determine the mechanism of cell number reduction, the effects of interferon alpha on murine hepatic progenitor cells were studied in vitro. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) proliferation assay and proliferating cell nuclear antigen staining showed that interferon alpha had a dose-dependent, anti-proliferative effect. Interferon alpha stimulated hepatocytic and biliary differentiation of the oval cell lines reflected by increased expression of albumin and cytokeratin19 accompanied by decreased expression of alphafetoprotein and Thy-1. To validate these results in vivo, mice were placed on the choline-deficient, ethionine-supplemented diet to induce liver injury and oval cell proliferation and treated with pegylated interferon alpha 2b for 2 weeks. This resulted in a significant four-fold reduction in the number of oval cells (P < .05). In conclusion, interferon alpha–based treatment reduced the number of hepatic progenitor cells in chronic liver injury by modulating apoptosis, proliferation, and differentiation.

Details

Title: Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo
Authors/Creators: Rebecca Lim (Author/Creator) - The University of Western Australia
Belinda Knight (Author/Creator) - The University of Western Australia
Keyur Patel (Author/Creator) - Duke University
John G. McHutchison (Author/Creator) - Duke University
George C. Yeoh (Author/Creator) - The University of Western Australia
John K. Olynyk (Author/Creator) - Fremantle Hospital
Publication Details: Hepatology, Vol.43(5), pp.1074-1083
Publisher: John Wiley & Sons Inc.
Identifiers: 991005542190607891
Copyright: © 2006 American Association for the Study of Liver Diseases
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.102 Stem Cell Research; 1.102.1150 Hepatocyte Growth Factor
Web Of Science research areas: Gastroenterology & Hepatology
ESI research areas: Clinical Medicine