TWEAK induces liver progenitor cell proliferation
Open accessAbstract
Progenitor ("oval") cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors.
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Monocytes and macrophages are key partners of reactive BECs, as macrophage-derived TWEAK is one of the initiating signals for ductular cell proliferation via the Fn14 receptor.
“Monocytes and macrophages are key partners of reactive BECs, as exemplified by studies indicating that macrophage-derived TWEAK is one of the initiating signals for ductular cell proliferation via the Fn14 receptor [167, 168].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [168]
Fn14 has been identified as a critical receptor for mitogenic stimulation of HPCs.
“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 [34]
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- Authors
- Jakubowski, A., Ambrose, C., Parr, M., Lincecum, J. M., Wang, M. Z., Zheng, T. S., Browning, B., Michaelson, J. S., Baestcher, M., Wang, B., Bissell, D. M., & Burkly, L. C.
- Affiliations
- Biogen (United States) (US)
- Oregon Health & Science University (US)
- University of California, San Francisco (US)
- Corresponding author
- Jakubowski, Aniela
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2005-09-01
- Volume
- 115
- Issue
- 9
- Pages
- 2330-2340
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1187931
- OpenAlex
- W2155189607
- Cited by
- 419
- References
- 56
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 17 · 2023: 9 · 2022: 14 · 2021: 10 · 2020: 15 · 2019: 17 · 2018: 22 · 2017: 20 · 2016: 28 · 2015: 29 · 2014: 26 · 2013: 40 · 2012: 26
- FWCI
- 12.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pittsburgh
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- TWEAK, Fn14, oval cells, liver progenitor cells, cell proliferation, liver regeneration, hepatocyte proliferation, chronic hepatitis C, liver injury, TNF family, DDC-induced liver injury
- MeSH terms
- Cytokine TWEAK, TWEAK Receptor, Adenoviridae, Animals, Female, Humans, Liver, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Stem Cells, Tissue Distribution, In Situ Hybridization, Receptors, Tumor Necrosis Factor, Mice, Knockout, Transgenes, Tumor Necrosis Factors, Cell Proliferation, Mice
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