Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice
Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice
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DOI：
10.1038/nbt1326
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发表时间：
2007-08-01
影响因子：
46.9
通讯作者：
Grompe, Markus
中科院分区：
文献类型：
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作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
可以用人类肝细胞高度繁殖的小鼠将在药物开发和研究应用中具有许多潜在用途。肝人源化的最佳可用模型，尿纤溶酶原激活剂转基因模型，具有主要的实际局限性。为了提供一个广泛有用的肝脏异种系统，我们产生了严重的免疫缺陷，延胡索酰乙酰乙酸水解酶（Fah）缺陷的小鼠。在用表达尿激酶的腺病毒预处理后，这些动物可以高度（高达90%）植入来自多种来源的人肝细胞，包括肝活检。此外，人类细胞可以从初级供体连续移植，并在至少四个连续轮中重新填充肝脏。扩增的细胞显示出典型的人类药物代谢。该系统提供了一个强大的平台，以产生高质量的人肝细胞的组织培养。它也可以用于测试药物代谢物的毒性和评估依赖于人类肝细胞复制的病原体。
Mice that could be highly repopulated with human hepatocytes would have many potential uses in drug development and research applications. The best available model of liver humanization, the uroplasminogen-activator transgenic model, has major practical limitations. To provide a broadly useful hepatic xenorepopulation system, we generated severely immunodeficient, fumarylacetoacetate hydrolase ( Fah)-deficient mice. After pretreatment with a urokinase-expressing adenovirus, these animals could be highly engrafted ( up to 90%) with human hepatocytes from multiple sources, including liver biopsies. Furthermore, human cells could be serially transplanted from primary donors and repopulate the liver for at least four sequential rounds. The expanded cells displayed typical human drug metabolism. This system provides a robust platform to produce high-quality human hepatocytes for tissue culture. It may also be useful for testing the toxicity of drug metabolites and for evaluating pathogens dependent on human liver cells for replication.