Early cell transplantation in LEC rats modeling Wilson's disease eliminates hepatic copper with reversal of liver disease
Early cell transplantation in LEC rats modeling Wilson's disease eliminates hepatic copper with reversal of liver disease
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DOI：
10.1053/gast.2002.31086
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发表时间：
2002-02-01
期刊：
影响因子：
29.4
通讯作者：
Gupta, S
中科院分区：
文献类型：
--
作者：
Malhi, H;Irani, AN;Gupta, S
背景与目的：Long-Evans Cinnamon (LEC) 大鼠是威尔逊氏病的优秀模型，具有铜排泄受损、低铜蓝蛋白血症和铜中毒的特点。我们假设早期肝细胞移植将改善威尔逊病中的铜排泄和肝脏疾病。方法：将正常同系 Long-Evans Agouti 大鼠肝细胞脾内移植到 2 周龄 LEC 大鼠体内。未经处理的 LEC 幼崽作为对照。肝脏再生通过血清铜蓝蛋白、肝脏 atp7b 信使 RNA 以及胆汁和肝脏铜水平的变化来显示。对肝脏进行组织学分析。结果：5 个月大的 LEC 大鼠中观察到明显的铜积累和肝脏疾病，偶尔治疗的大鼠显示胆汁铜排泄增加。细胞移植后 20 个月，14 只治疗 LEC 大鼠中的 10 只 (71%) 肝脏广泛重新增殖。在这 10 只大鼠中，与未经治疗的 LEC 大鼠肝铜水平升高 (1090 +/- 253 mug/g) 相比，6 只大鼠的肝铜含量实际上正常 (53 +/- 12 mug/g 肝脏)，而其他 4 只大鼠 (270 +/- 35 mug/g) 的肝铜含量明显较低 (P < 0.001)。血清铜蓝蛋白水平、胆汁铜排泄能力和肝脏组织学的变化与肝铜水平的降低一致。结论：移植细胞在肝损伤发生后增殖，并且肝脏在较长时间内重新增殖。细胞移植最终在 LEC 大鼠中恢复了铜稳态并逆转了肝脏疾病，而无需进行肝脏预处理。
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 mug/g liver) and substantially less in 4 others (270 +/- 35 mug/g) compared with elevated liver copper levels in untreated LEC rats (1090 +/- 253 mug/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.