title: Early cell transplantation in LEC rats modeling Wilson's disease eliminates hepatic copper with reversal of liver disease.
abstract: OBJECTIVE
  The Long-Evans Cinnamon (LEC) rat is an excellent model of Wilson's disease with impaired copper excretion, hypoceruloplasminemia, and copper toxicosis. We hypothesized that early hepatocyte transplantation would improve copper excretion and liver disease in Wilson's disease.
  
  
  METHODS
  Normal syngeneic Long-Evans Agouti rat hepatocytes were transplanted intrasplenically into 2-week-old LEC rats. Untreated LEC pups were controls. Liver repopulation was shown by changes in serum ceruloplasmin, hepatic atp7b messenger RNA, and bile and liver copper levels. Histologic analysis of the liver was performed.
  
  
  RESULTS
  Significant copper accumulation and liver disease were observed in 5-month-old LEC rats, with occasional treated rats showing increased bile copper excretion. The liver was repopulated extensively in 10 of 14 treated LEC rats (71%) 20 months after cell transplantation. In these 10 rats, hepatic copper content was virtually normal in 6 rats (53 +/- 12 microg/g liver) and substantially less in 4 others (270 +/- 35 microg/g) compared with elevated liver copper levels in untreated LEC rats (1090 +/- 253 microg/g) (P < 0.001). Changes in serum ceruloplasmin levels, bile copper excretion capacity, and liver histology were in concordance with decreases in liver copper levels.
  
  
  CONCLUSIONS
  Transplanted cells proliferated subsequent to the onset of liver injury, and the liver was repopulated over an extended period. Cell transplantation eventually restored copper homeostasis and reversed liver disease without hepatic preconditioning in LEC rats.
authors.affiliation: Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Malhi
authors.forename: Adil N
authors.initials: AN
authors.lastname: Irani
authors.forename: Irene
authors.initials: I
authors.lastname: Volenberg
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schilsky
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D003300:Copper / Q000378:metabolism*; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000637:transplantation*; D006527:Hepatolenticular Degeneration / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051381:Rats; D020332:Rats, Inbred LEC
chemical_list: D003300:Copper