The DOI matches its Crossref record; 50 of the 53 references it cites were found in a registry or an index.
Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells
Open accessAbstract
Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor–like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin–positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NFκB subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NFκB-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration. (Hepatology 2010)
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“Fn14 has been identified as a critical receptor for mitogenic stimulation of HPCs31-34.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [33]
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“HPCs had a corresponding reduction in NFκB activity (Figure 5g), a downstream mediator of TWEAK-Fn14 signalling33.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [33]
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Citations
Cites
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TWEAK, a New Secreted Ligand in the Tumor Necrosis Factor Family That Weakly Induces Apoptosis
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The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting
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Oval Cell Numbers in Human Chronic Liver Diseases Are Directly Related to Disease Severity
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- TirnitzParker, 2007, Isolation, culture and immortalisation of hepatic oval cells from adult mice fed a cholinedeficient, ethioninesupplemented diet., Int J Biochem Cell Biol, 39, 22262239
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Aggarwal, B. B., Gupta, S. C., & Kim, J. H. (2012) · Blood · doi:10.1182/blood-2011-04-325225 · Cited by 877
The TNF Family of Ligands and Receptors: Communication Modules in the Immune System and Beyond
Dostert, C., Grusdat, M., Letellier, E., & Brenner, D. (2018) · Physiological Reviews · doi:10.1152/physrev.00045.2017 · Cited by 529
Hepatic progenitor cells of biliary origin with liver repopulation capacity
Lu, W.-Y., Bird, T. G., Boulter, L., Tsuchiya, A., Cole, A. M., Hay, T., Guest, R. V., Wojtacha, D., Man, T. Y., Mackinnon, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3203 · Cited by 479
The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease
Gadd, V. L., Skoien, R., Powell, E. E., Fagan, K. J., Winterford, C., Horsfall, L., Irvine, K., & Clouston, A. D. (2014) · Hepatology · doi:10.1002/hep.26937 · Cited by 452
Ductular reaction in liver diseases: pathological mechanisms and translational significances
Sato, K., Marzioni, M., Meng, F., Francis, H., Glaser, S., & Alpini, G. (2019) · Hepatology · doi:10.1002/hep.30150 · Cited by 423
“A study has shown that CDE diet induces elevated Fn14 expression in the liver and Fn14 is colocalized with panCK.(68) This study has also demonstrated that Fn14 knockout mice show less DR (A6+ or CK19+ cell counts) during CDE diet compared with wildtype, and treatments of TWEAK, which is an Fn14 ligand, induce prolife…”
Background
Metadata
- Authors
- Tirnitz-Parker, J. E. E., Viebahn, C. S., Jakubowski, A., Klopcic, B. R. S., Olynyk, J. K., Yeoh, G. C. T., & Knight, B.
- Affiliations
- The University of Western Australia (AU)
- Biogen (United States) (US)
- Centre for Inflammation Research (GB)
- Venue
- Hepatology
- Published
- 2010-07
- Volume
- 52
- Issue
- 1
- Pages
- 291-302
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2005176562
- Cited by
- 177
- References
- 53
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 3 · 2022: 10 · 2021: 9 · 2020: 11 · 2019: 7 · 2018: 6 · 2017: 18 · 2016: 18 · 2015: 15 · 2014: 18 · 2013: 20 · 2012: 16
- FWCI
- 9.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Murdoch University Research Portal (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- Funders
- University of Edinburgh
- Gastroenterological Society of Australia
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- TWEAK, Fn14, liver progenitor cells, chronic liver injury, liver regeneration, cell proliferation, NF-κB signaling, p50 subunit, hepatic stellate cells, liver fibrosis, choline-deficient ethionine-supplemented diet, cytokine production, inflammation
- MeSH terms
- Cytokine TWEAK, TWEAK Receptor, Animals, Choline Deficiency, Collagen, Ethionine, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Mitogens, Mitosis, Recombinant Proteins, Stem Cells, NF-kappa B, Receptors, Tumor Necrosis Factor, Mice, Knockout, Tumor Necrosis Factors, Cell Proliferation, Mice
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