title: Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.
abstract: BACKGROUND
  Hepatocyte transplantation (HT) is a promising alternative treatment strategy for end-stage liver diseases compared with orthotopic liver transplantation. A limitation for this approach is the low engraftment of donor cells. The deletion of the I-kappa B kinase-regulatory subunit IKKγ/NEMO in hepatocytes prevents nuclear factor (NF)-kB activation and triggers spontaneous liver apoptosis, chronic hepatitis and the development of liver fibrosis and hepatocellular carcinoma. We hypothesized that NEMOΔhepa mice may therefore serve as an experimental model to study HT.
  
  
  METHODS
  Pre-conditioned NEMOΔhepa mice were transplanted with donor-hepatocytes from wildtype (WT) and mice deficient for the pro-apoptotic mediator Caspase-8 (Casp8Δhepa).
  
  
  RESULTS
  Transplantation of isolated WT-hepatocytes into pre-conditioned NEMOΔhepa mice resulted in a 6-7 fold increase of donor cells 12 weeks after HT, while WT-recipients showed no liver repopulation. The use of apoptosis-resistant Casp8Δhepa-derived donor cells further enhanced the selection 3-fold after 12-weeks and up to 10-fold increase after 52 weeks compared with WT donors. While analysis of NEMOΔhepa mice revealed strong liver injury, HT-recipient NEMOΔhepa mice showed improved liver morphology and decrease in serum transaminases. Concomitant with these findings, the histological examination elicited an improved liver tissue architecture associated with significantly lower levels of apoptosis, decreased proliferation and a lesser amount of liver fibrogenesis. Altogether, our data clearly support the therapeutic benefit of the HT procedure into NEMOΔhepa mice.
  
  
  CONCLUSIONS
  This study demonstrates the feasibility of the NEMOΔhepa mouse as an in vivo tool to study liver repopulation after HT. The improvement of the characteristic phenotype of chronic liver injury in NEMOΔhepa mice after HT suggests the therapeutic potential of HT in liver diseases with a chronic inflammatory phenotype and opens a new door for the applicability of this technique to combat liver disease in the human clinic.
authors: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Michaela
authors: M
authors: Kaldenbach
authors: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Francisco Javier
authors: FJ
authors: Cubero
authors: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Stephanie
authors: S
authors: Erschfeld
authors: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Christian
authors: C
authors: Liedtke
authors: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Christian
authors: C
authors: Trautwein
authors: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Konrad
authors: K
authors: Streetz
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D017353:Gene Deletion; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D000637:Transaminases / Q000097:blood; D014184:Transplantation, Homologous
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D000637:Transaminases; C505526:Casp8 protein, mouse; D053181:Caspase 8