title: Hepatocyte transplantation in the Long Evans Cinnamon rat model of Wilson's disease.
abstract: Wilson's disease (WD), caused by a mutation in the P-type copper transporting ATPase (Atp7b) gene, results in excessive accumulation of copper in the liver. Long Evans Cinnamon rats (LEC) bear a mutation in the atp7b gene and share clinical characteristics of human WD. To explore hepatocyte transplantation (HT) as therapy for metabolic liver diseases, 8-week-old LEC rats (n = 12) were transplanted by intrasplenic injection of hepatocytes from donor Long Evans (LE) rats. Immunosuppression was maintained with intraperitoneal tacrolimus. The success of HT was monitored at 24 weeks of life. Serum aminotransferases and bilirubin peaked at 14-21 weeks in both HT rats and nontransplanted controls, but at 24 weeks, survival was 97% in LEC-HT versus 63% in controls. All transplanted rats showed restored biliary copper excretion and reduced liver iron concentration associated with increased ceruloplasmin oxidase activity. Liver tissue expressed atp7b mRNA (11.9 +/- 13.6%) indicative of engraftment of normal cells in 7 of 12 HT rats, associated with a reduced liver copper concentration compared to untreated LEC rats. Periportal islets of normal appearing hepatocytes, recognized by atp7b antibody, were observed in transplanted livers while lobular host cells showed persistent pleomorphic changes and inflammatory infiltrates. In conclusion, transplantation of normal hepatocytes prevented fulminant hepatitis, reduces chronic inflammation, and improved 6-month survival in LEC rats. Engraftment of transplanted cells, which express atp7b mRNA, repopulated the recipient liver with normal functional capacity.
authors.affiliation: Department of Pediatrics, Hôpital Sainte-Justine, Université de Montréal, Montréal, Qc, Canada.
authors.forename: Seon Mee
authors.initials: SM
authors.lastname: Park
authors.forename: Kim
authors.initials: K
authors.lastname: Vo
authors.forename: Michel
authors.initials: M
authors.lastname: Lallier
authors.forename: Alexis-Simon
authors.initials: AS
authors.lastname: Cloutier
authors.forename: Pierre
authors.initials: P
authors.lastname: Brochu
authors.forename: Fernando
authors.initials: F
authors.lastname: Alvarez
authors.forename: Steven R
authors.initials: SR
authors.lastname: Martin
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D003300:Copper / Q000032:analysis; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D005260:Female; D006085:Graft Survival; D022781:Hepatocytes / Q000201:enzymology / Q000637:transplantation*; D006527:Hepatolenticular Degeneration / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D007278:Injections, Spinal; D007501:Iron / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D008297:Male; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020332:Rats, Inbred LEC; D013154:Spleen / Q000166:cytology; D015996:Survival Rate; D014184:Transplantation, Homologous
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; D003300:Copper; D007501:Iron; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases