title: Control of hepatocyte proliferation and survival  by Fgf receptors is essential for liver regeneration  in mice.
abstract: OBJECTIVE
  Fibroblast growth factors (Fgfs) are key orchestrators of development, and a role of Fgfs in tissue repair is emerging. Here we studied the consequences of inducible loss of Fgf receptor (Fgfr) 4, the major Fgf receptor (Fgfr) on hepatocytes, alone or in combination with Fgfr1 and Fgfr2, for liver regeneration after PH.
  
  
  METHODS
  We used siRNA delivered via nanoparticles combined with liver-specific gene knockout to study Fgfr function in liver regeneration. Liver or blood samples were analysed using histology, immunohistochemistry,real-time RT-PCR, western blotting and ELISA.
  
  
  RESULTS
  siRNA-mediated knockdown of Fgfr4 severely affected liver regeneration due to impairment of hepatocyte proliferation combined with liver necrosis.Mechanistically, the proliferation defect resulted from inhibition of an Fgf15-Fgfr4-Stat3 signalling pathway,which is required for injury-induced expression of the Foxm1 transcription factor and subsequent cell cycle progression, while elevated levels of intrahepatic toxicbile acids were identified as the likely cause of the necrotic damage. Failure of liver mass restoration in Fgfr4 knockdown mice was prevented at least in part by compensatory hypertrophy of hepatocytes. Most importantly, our data revealed partially redundant functions of Fgf receptors in the liver, since knock down of Fgfr4 in mice lacking Fgfr1 and Fgfr2 in hepatocytes caused liver failure after PH due to severe liver necrosis and a defect in regeneration.
  
  
  CONCLUSIONS
  These results demonstrate that Fgfr signalling in hepatocytes is essential for liver regeneration and suggest activation of Fgfr signalling asa promising approach for the improvement of the liver's regenerative capacity.
authors.forename: Susagna
authors.initials: S
authors.lastname: Padrissa-Altés
authors.forename: Marc
authors.initials: M
authors.lastname: Bachofner
authors.forename: Roman L
authors.initials: RL
authors.lastname: Bogorad
authors.forename: Lea
authors.initials: L
authors.lastname: Pohlmeier
authors.forename: Thomas
authors.initials: T
authors.lastname: Rossolini
authors.forename: Friederike
authors.initials: F
authors.lastname: Böhm
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Tobias
authors.initials: T
authors.lastname: Speicher
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018709:Statistics, Nonparametric
chemical_list: D016207:Cytokines; D034741:RNA, Small Interfering; D051499:Receptor, Fibroblast Growth Factor, Type 4