BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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: Ryan C Gessner; Ariel D Hanson; Steven Feingold; Avery T Cashion; Ana Corcimaru; Bryant T Wu; Christopher R Mullins; Stephen R Aylward; Lola M Reid; Paul A Dayton Journal: Biomaterials Date: 2013-09-04 Impact factor: 12.479
Authors: Harmeet Malhi; Giridhar R Gorla; Adil N Irani; Pallavi Annamaneni; Sanjeev Gupta Journal: Proc Natl Acad Sci U S A Date: 2002-09-20 Impact factor: 11.205