title: Hepatocyte growth factor/c-Met signalling is important for the selection of transplanted hepatocytes.
abstract: BACKGROUND
  At present hepatocyte transplantation is a promising option for cellular therapy of end-stage liver diseases. However, the underlying molecular mechanisms need to be better defined in order to translate this technique into clinical use. This study investigated the cursiv relevance of hepatocyte growth factor (HGF)/c-Met signalling for hepatocyte repopulation after transplantion.
  
  
  METHODS
  Wild-type mice (c-Met(loxP/loxP)) and hepatocyte-specific conditional c-Met (HGF receptor) knockout (c-Met(Δhepa)) mice were used as donors and recipients for hepatocyte transplantation.
  
  
  RESULTS
  Transplantation experiments revealed two major findings. First it was demonstrated that c-Met is indispensable in donor cells, as c-Met(Δhepa) cells did not repopulate recipient livers after transplantation. Second, genetic deletion of c-Met in recipient hepatocytes resulted in enhanced expansion of unmodified donor cells in host livers (up to 250-fold after 12 weeks). The relevant mechanisms for this observation in c-Met(Δhepa) host hepatocytes could be defined. c-Met(Δhepa) hepatocytes showed enhanced apoptosis, reduced cellular proliferation and a lack of AKT-kinase and STAT3 activation. In addition, tissue remodelling was changed in c-Met(Δhepa) recipient livers. Therefore, the lack of pro-proliferative transcription factors, increased apoptosis and changes in matrix-remodelling inhibit host cell proliferation in c-Met(Δhepa) recipient livers and thus favour repopulation of transplanted hepatocytes. Therapeutically liver repopulation could be increased through adenoviral expression of NK-4--an inhibitor of HGF signalling--in host hepatocytes.
  
  
  CONCLUSIONS
  HGF/c-Met plays a crucial role in host and donor cells of the liver for the cursiv selection of transplanted hepatocytes. Modulating HGF-dependent signalling seems a promising therapeutic option to favour expansion of transplanted hepatocytes.
authors.affiliation: Department of Medicine III, RWTH Aachen University, Aachen, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kaldenbach
authors.forename: Arne
authors.initials: A
authors.lastname: Giebeler
authors.forename: Darjus F
authors.initials: DF
authors.lastname: Tschaharganeh
authors.forename: Stephanie
authors.initials: S
authors.lastname: Erschfeld
authors.forename: Hermann E
authors.initials: HE
authors.lastname: Wasmuth
authors.forename: Laurent
authors.initials: L
authors.lastname: Dolle
authors.forename: Juergen
authors.initials: J
authors.lastname: Floege
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Konrad L
authors.initials: KL
authors.lastname: Streetz
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002450:Cell Communication; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation*; D020287:In Situ Nick-End Labeling; D017093:Liver Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases