TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice.


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.





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Publication Info

Karaca, Gamze, Marzena Swiderska-Syn, Guanhua Xie, Wing-Kin Syn, Leandi Krüger, Mariana Verdelho Machado, Katherine Garman, Steve S Choi, et al. (2014). TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice. PLoS One, 9(1). p. e83987. 10.1371/journal.pone.0083987 Retrieved from

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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 damaged, and with cancer.


Steven Sok Choi

Associate Professor of Medicine

Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration

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