title: Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis.
abstract: OBJECTIVE
  Patients with progressive familial intrahepatic cholestasis (PFIC) type 3 have a mutation in the MDR3 gene, encoding the hepatocanalicular phospholipid translocator. In general, liver failure develops within the first decade of life in these patients. Previous studies have shown that in the mdr2-knockout mouse, the animal model for this disease, the absence of phospholipids in bile causes chronic bile salt-induced damage to hepatocytes. We aimed to test the efficacy of hepatocyte transplantation and liver repopulation in this disease model.
  
  
  METHODS
  Transgenic MDR3-expressing hepatocytes as well as normal mdr2(+/+) hepatocytes were transplanted in mdr2(-/-) mice, and liver repopulation was assessed by immunohistochemistry and measurement of biliary lipid secretion.
  
  
  RESULTS
  Transplanted hepatocytes partially repopulated the liver, restored phospholipid secretion, and diminished liver pathology. Repopulation was stronger when hepatocellular damage was enhanced by a bile salt-supplemented diet. After 1 year, however, these animals developed multiple hepatic tumors, and biliary phospholipid secretion decreased. In transplanted animals receiving a control diet, repopulation was slower but eventually remained stable at 21%, while liver pathology was completely abrogated and tumor formation was prevented.
  
  
  CONCLUSIONS
  These results suggest that moderate liver pathology is a safe condition for the induction of effective hepatocyte repopulation and that this therapy is potentially applicable to patients with PFIC type 3.
authors: Laboratory for Experimental Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors: J M
authors: JM
authors: De Vree
authors: R
authors: R
authors: Ottenhoff
authors: P J
authors: PJ
authors: Bosma
authors: A J
authors: AJ
authors: Smith
authors: J
authors: J
authors: Aten
authors: R P
authors: RP
authors: Oude Elferink
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D020355:Cholates / Q000008:administration & dosage / Q000494:pharmacology; D002779:Cholestasis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D004032:Diet; D022781:Hepatocytes / Q000637:transplantation*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D010743:Phospholipids / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D020355:Cholates; D010743:Phospholipids; C095122:multidrug resistance protein 3