TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice.
Abstract
BACKGROUND & AIMS: Pro-inflammatory cytokines are important for liver regeneration
after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14
(Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly
after PH and remains elevated throughout the period of peak hepatocyte replication.
The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed
by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but
replication of mature hepatocytes is thought to drive liver regeneration after PH.
METHODS: To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative
responses in wild type (WT) mice, Fn14 knockout (KO) mice, TWEAK KO mice, and WT mice
treated with anti-TWEAK antibodies. RESULTS: In WT mice, rare Fn14(+) cells localized
with other progenitor markers in peri-portal areas before PH. PH rapidly increased
proliferation of Fn14(+) cells; hepatocytic cells that expressed Fn14 and other progenitor
markers, such as Lgr5, progressively accumulated from 12-8 h post-PH and then declined
to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation,
induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation,
and over-all survival were inhibited, while post-PH liver damage and bilirubin levels
were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured
liver progenitors, but had no effect on either parameter in cultured primary hepatocytes.
CONCLUSIONS: TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate
normally after acute partial hepatectomy.
Type
Journal articleSubject
AnimalsAntibodies
Cell Proliferation
Epithelial Cells
Gene Deletion
Hepatectomy
Hepatocytes
Liver
Liver Regeneration
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitogens
Receptors, Tumor Necrosis Factor
Signal Transduction
Tumor Necrosis Factors
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https://hdl.handle.net/10161/11083Published Version (Please cite this version)
10.1371/journal.pone.0083987Publication Info
Karaca, Gamze; Swiderska-Syn, Marzena; Xie, Guanhua; Syn, Wing-Kin; Krüger, Leandi;
Machado, Mariana Verdelho; ... Diehl, Anna Mae (2014). TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy
in mice. PLoS One, 9(1). pp. e83987. 10.1371/journal.pone.0083987. Retrieved from https://hdl.handle.net/10161/11083.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Steven Sok Choi
Associate Professor of Medicine
Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration
Anna Mae Diehl
Florence McAlister Distinguished Professor of Medicine
Our lab has a long standing interest in liver injury and repair. To learn more about
the mechanisms that regulate this process, we study cultured cells, animal models
of acute and chronic liver damage and samples from patients with various types of
liver disease. Our group also conducts clinical trials in patients with chronic liver
disease. We are particularly interested in fatty liver diseases, such as alcoholic
fatty liver disease and nonalcoholi
Katherine Schuver Garman
Associate Professor of Medicine
My research focuses on injury, repair, and cancer development in the gastrointestinal
tract. My laboratory performs translational research with the goal of improving health
of the gastrointestinal tract. Our work is based in observations from human clinical
research. We use databases of esophageal and colon disease to learn more about clinical
risk factors for disease. We also use pathology samples of tumors to study the gastrointestinal
tract in different states: healthy, inflamed or da
Gregory Alexander Michelotti
Associate Professor in Medicine
The goal of my research is to elucidate mechanisms underlying catecholamine-induced
myocardial hypertrophy and identify unique pathways directing adaptive (physiologic)
versus maladaptive (pathologic) responses. Stimulation of α1aAR has been shown
to mediate myocardial hypertrophy, culminating in both morphological and genetic cellular
changes, however it is unknown if α1ARs simply trigger initial hypertrophic events
or rather preferentially activate adaptive
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