title: TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Gamze
authors.initials: G
authors.lastname: Karaca
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Marzena
authors.initials: M
authors.lastname: Swiderska-Syn
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xie
authors.affiliation: Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, United Kingdom ; Department of Hepatology, Barts Health NHS Trust, London, United Kingdom.
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Syn
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Leandi
authors.initials: L
authors.lastname: Krüger
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Mariana Verdelho
authors.initials: MV
authors.lastname: Machado
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Garman
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Steve S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Departments of Exploratory Science, Discovery Biology, and Validation Biology, Biogen Idec Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Department of Physiology, Faculty of Medicine, University of the Basque Country, Bilbao, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Ochoa
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D000074049:Cytokine TWEAK; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D017353:Gene Deletion; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000601:surgery*; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008934:Mitogens / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000074049:Cytokine TWEAK; D008934:Mitogens; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors