Optimized HepaRG is a suitable cell source to generate the human liver chimeric mouse model for the chronic hepatitis B virus infection.
Optimized HepaRG is a suitable cell source to generate the human liver chimeric mouse model for the chronic hepatitis B virus infection.
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DOI：
10.1038/s41426-018-0143-9
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发表时间：
2018-08-10
影响因子：
13.2
通讯作者：
Xia N
中科院分区：
文献类型：
--
作者：
Yuan L;Liu X;Zhang L;Zhang Y;Chen Y;Li X;Wu K;Cao J;Hou W;Que Y;Zhang J;Zhu H;Yuan Q;Tang Q;Cheng T;Xia N
原代人肝细胞（PHH）移植人肝嵌合体小鼠是研究B肝炎病毒（HBV）致病机制和评价抗HBV药物的理想动物模型。然而，使用PHH的缺点包括不能在体外进行细胞扩增，供体可用性有限，个体差异和伦理问题，需要开发替代品。为了获得体外可扩增的肝细胞，我们优化了人肝祖细胞系HepaRG的肝分化程序，使用四种功能性小分子（4SM），并富集了前体肝细胞样细胞（HLC）。将不同肝分化状态的HepaRG细胞移植到免疫缺陷小鼠（FRGS）中，每周进行一次4SM治疗。HepaRG移植小鼠用HBV激发和/或用几种抗病毒药治疗以评价其作用。我们证明，4SM处理增强肝分化，促进细胞增殖能力，在体外和体内。用肝前分化的富集HepaRG移植并用4SM处理的小鼠在移植后第8周显示出约10%的肝嵌合体，并在该水平下维持另外16周。因此，我们开发了基于HepaRG的人肝嵌合小鼠模型：HepaRG-FRGS。我们的实验结果表明，小鼠的肝脏嵌合体足以支持慢性HBV感染24周，并评估抗病毒药物。我们还证明，HBV感染HepaRG细胞是依赖于他们的肝分化状态和肝嵌合体在体内。总之，HepaRG-FRGS小鼠提供了一种新的人肝嵌合小鼠模型，用于研究慢性HBV感染和评估抗HBV药物。
The human liver chimeric mouse with primary human hepatocytes (PHHs) engraftment has been demonstrated to be a useful animal model to study hepatitis B virus (HBV) pathogenesis and evaluate anti-HBV drugs. However, the disadvantages of using PHHs include the inability for cellular expansion in vitro, limited donor availability, individual differences, and ethical issues, necessitating the development of alternatives. To obtain in vitro expandable hepatocytes, we optimized the hepatic differentiation procedure of the human liver progenitor cell line, HepaRG, using four functional small molecules (4SM) and enriched the precursor hepatocyte-like cells (HLCs). HepaRG cells of different hepatic differentiation states were engrafted to immunodeficient mice (FRGS) with weekly 4SM treatment. The HepaRG-engrafted mice were challenged with HBV and/or treated with several antivirals to evaluate their effects. We demonstrated that the 4SM treatment enhanced hepatic differentiation and promoted cell proliferation capacity both in vitro and in vivo. Mice engrafted with enriched HepaRG of prehepatic differentiation and treated with 4SM displayed approximately 10% liver chimerism at week 8 after engraftment and were maintained at this level for another 16 weeks. Therefore, we developed a HepaRG-based human liver chimeric mouse model: HepaRG-FRGS. Our experimental results showed that the liver chimerism of the mice was adequate to support chronic HBV infection for 24 weeks and to evaluate antivirals. We also demonstrated that HBV infection in HepaRG cells was dependent on their hepatic differentiation state and liver chimerism in vivo. Overall, HepaRG-FRGS mice provide a novel human liver chimeric mouse model to study chronic HBV infection and evaluate anti-HBV drugs.
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影响因子：
6.7
作者：
Bility MT;Cheng L;Zhang Z;Luan Y;Li F;Chi L;Zhang L;Tu Z;Gao Y;Fu Y;Niu J;Wang F;Su L
通讯作者：
Su L
影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
DOI：
10.3109/00498254.2013.836257
发表时间：
2014-01
期刊：
Xenobiotica; the fate of foreign compounds in biological systems
影响因子：
--
作者：
Higuchi Y;Kawai K;Yamazaki H;Nakamura M;Bree F;Guguen-Guillouzo C;Suemizu H
通讯作者：
Suemizu H
影响因子：
5.4
作者：
Köck, J;Nassal, M;von Weizsäcker, F
通讯作者：
von Weizsäcker, F
影响因子：
5.4
作者：
GRIPON, P;DIOT, C;GUGUENGUILLOUZO, C
通讯作者：
GUGUENGUILLOUZO, C