TWEAK induces liver progenitor cell proliferation.
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.
Jakubowski
Aniela
A
Department of Exploratory Science, Biogen Idec Inc., Cambridge, Massachusetts 02142, USA. Aniela.Jakubowski@biogenidec.com
Ambrose
Christine
C
Parr
Michael
M
Lincecum
John M
JM
Wang
Monica Z
MZ
Zheng
Timothy S
TS
Browning
Beth
B
Michaelson
Jennifer S
JS
Baetscher
Manfred
M
Baestcher
Manfred
M
Wang
Bruce
B
Bissell
D Montgomery
DM
Burkly
Linda C
LC
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D000074049:Cytokine TWEAK; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D000074050:TWEAK Receptor; D014018:Tissue Distribution; D019076:Transgenes; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors