TY - JOUR
T1 - Early cell transplantation in LEC rats modeling Wilson's disease eliminates hepatic copper with reversal of liver disease
AU - Malhi, Harmeet
AU - Irani, Adil N.
AU - Gupta, Sanjeev
AU - Volenberg, Irene
AU - Schilsky, Michael L.
PY - 2002
Y1 - 2002
N2 - 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 μg/g liver) and substantially less in 4 others (270 ± 35 μg/g) compared with elevated liver copper levels in untreated LEC rats (1090 ± 253 μg/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.
AB - 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 μg/g liver) and substantially less in 4 others (270 ± 35 μg/g) compared with elevated liver copper levels in untreated LEC rats (1090 ± 253 μg/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.
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U2 - 10.1053/gast.2002.31086
DO - 10.1053/gast.2002.31086
M3 - Article
C2 - 11832458
AN - SCOPUS:0036158844
SN - 0016-5085
VL - 122
SP - 438
EP - 447
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -