title: Liver failure after extended hepatectomy in mice is mediated by a p21-dependent barrier to liver regeneration.
abstract: OBJECTIVE
  Extended liver resection leads to hepatic failure because of a small remnant liver volume. Excessive parenchymal damage has been proposed as the principal cause of this failure, but little is known about the contribution of a primary deficiency in liver regeneration. We developed a mouse model to assess the regenerative capacity of a critically small liver remnant.
  
  
  METHODS
  Extended (86%) hepatectomy (eHx) was modified to minimize collateral damage; effects were compared with those of standard (68%) partial hepatectomy (pHx) in mice. Markers of liver integrity and survival were evaluated after resection. Liver regeneration was assessed by weight gain, proliferative activity (analyses of Ki67, proliferating cell nuclear antigen, phosphorylated histone 3, mitosis, and ploidy), and regeneration-associated molecules. Knockout mice were used to study the role of p21.
  
  
  RESULTS
  Compared with pHx, survival of mice was reduced after eHx, and associated with cholestasis and impaired liver function. However, no significant differences in hepatocyte death, sinusoidal injury, oxidative stress, or energy depletion were observed between mice after eHx or pHx. No defect in the initiation of hepatocyte proliferation was apparent. However, restoration of liver mass was delayed after eHx and associated with inadequate induction of Foxm1b and a p21-dependent delay in cell-cycle progression. In p21(-/-) mice, the cell cycle was restored, the gain in liver weight was accelerated, and survival improved after eHx.
  
  
  CONCLUSIONS
  Significant parenchymal injury is not required for liver failure to develop after extended hepatectomy. Rather, liver dysfunction after eHx results from a transient, p21-dependent block before hepatocyte division. Therefore, a deficiency in cell-cycle progression causes liver failure after extended hepatectomy and can be overcome by inhibition of p21.
authors.affiliation: Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Kuno
authors.initials: K
authors.lastname: Lehmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Tschuor
authors.forename: Andreas
authors.initials: A
authors.lastname: Rickenbacher
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.forename: Christian E
authors.initials: CE
authors.lastname: Oberkofler
authors.forename: Oliver
authors.initials: O
authors.lastname: Tschopp
authors.forename: Simon M
authors.initials: SM
authors.lastname: Schultze
authors.forename: Dimitri A
authors.initials: DA
authors.lastname: Raptis
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology; D006498:Hepatectomy / Q000009:adverse effects*; D008099:Liver / Q000503:physiopathology / Q000601:surgery*; D017093:Liver Failure / Q000209:etiology* / Q000503:physiopathology*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000502:physiology
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse