A Chimeric Humanized Mouse Model by Engrafting the Human Induced Pluripotent Stem Cell-Derived Hepatocyte-Like Cell for the Chronic Hepatitis B Virus Infection.
A Chimeric Humanized Mouse Model by Engrafting the Human Induced Pluripotent Stem Cell-Derived Hepatocyte-Like Cell for the Chronic Hepatitis B Virus Infection.
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DOI：
10.3389/fmicb.2018.00908
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发表时间：
2018
影响因子：
5.2
通讯作者：
Xia N
中科院分区：
文献类型：
--
作者：
Yuan L;Liu X;Zhang L;Li X;Zhang Y;Wu K;Chen Y;Cao J;Hou W;Zhang J;Zhu H;Yuan Q;Tang Q;Cheng T;Xia N
将原代人肝细胞(PHHs)移植到免疫缺陷小鼠建立人源化小鼠模型，对了解乙肝病毒的发病机制具有重要意义。然而，PHHs的来源是有限的，这就需要寻找替代品。近年来，由人诱导多能干细胞(HiPSCs)诱导产生的肝细胞样细胞(HLCs)已被用于体外感染乙肝病毒。在此，我们通过将hPSC-hLCs移植到Fah-/-RAG2-/-IL-2Rγc-/-SCID(FRGS)小鼠体内，建立了一种强大的人肝嵌合动物模型来研究体内的乙肝病毒感染。经小分子XMU-MP-1优化后，植入FRGS(hHLC-FRGS)的HiPSC-HLCs小鼠在移植后6周表现出约40%的肝脏嵌合体，并保持在这一水平至少14周。在感染了乙肝病毒的hHLC-FRGS小鼠中可检测到病毒血症和包括抗原、RNA、DNA和共价闭合环状DNA在内的乙肝病毒感染标志物。此外，还成功地利用hPSC-HLCs和hHLC-FRGS小鼠评价了不同的抗病毒药物。因此，我们建立了一种人源化的小鼠模型，不仅可以研究乙肝病毒的发病机制，还可以检测抗乙肝药物的作用。亮点：(1)植入的HiPSC-HLCs在FRGS小鼠肝脏中建立了长期的嵌合体。他们(2)hHLC-FRGS小鼠足以支持具有完整病毒生命周期的慢性乙肝病毒感染。结果(3)hPSC-HLCs和hHLC-FRGS小鼠是体内外评价抗病毒药物的有用工具。背景研究为了克服使用原代人类肝细胞的缺点，我们将人多能干细胞诱导为肝细胞样细胞(hiPSC-HLCs)，使其能够表达重要的肝功能标志和关键的乙肝病毒感染宿主因子。HiPSC-HLCs对乙肝病毒感染是允许的，并支持完全复制乙肝病毒。然后将hPSC-HLCs移植到免疫缺陷小鼠体内建立嵌合肝小鼠模型，该模型能够支持体内乙肝病毒感染并评价抗病毒药物的效果。我们的结果有助于改进研究乙肝病毒和其他嗜肝病毒的细胞和动物模型。
Humanized mouse model generated by grafting primary human hepatocytes (PHHs) to immunodeficient mouse has contributed invaluably to understanding the pathogenesis of hepatitis B virus (HBV). However, the source of PHHs is limited, which necessitates the search for alternatives. Recently, hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells (hiPSCs) have been used for in vitro HBV infection. Herein, we developed a robust human liver chimeric animal model to study in vivo HBV infection by engrafting the hiPSC-HLCs to Fah-/-Rag2-/-IL-2Rγc-/- SCID (FRGS) mice. After being optimized by a small molecule, XMU-MP-1, the hiPSC-HLCs engrafted FRGS (hHLC-FRGS) mice displayed approximately 40% liver chimerism at week 6 after engraftment and maintained at this level for at least 14 weeks. Viremia and HBV infection markers include antigens, RNA, DNA, and covalently closed circular DNA were detectable in HBV infected hHLC-FRGS mice. Furthermore, hiPSC-HLCs and hHLC-FRGS mice were successfully used to evaluate different antivirals. Therefore, we established a humanized mouse model for not only investigating HBV pathogenesis but also testing the effects of the anti-HBV drugs. Highlights: (1) The implanted hiPSC-HLCs established a long-term chimerism in FRGS mice liver. (2) hHLC-FRGS mice are adequate to support chronic HBV infection with a full viral life cycle. (3) hiPSC-HLCs and hHLC-FRGS mice are useful tools for evaluation of antivirals against HBV infection in vitro and in vivo. Research in Context To overcome the disadvantages of using primary human hepatocytes, we induced human pluripotent stem cells to hepatocyte-like cells (hiPSC-HLCs) that developed the capability to express important liver functional markers and critical host factors for HBV infection. The hiPSC-HLCs were permissive for the HBV infection and supported a full HBV replication. The hiPSC-HLCs were then engrafted to immunodeficient mouse to establish a chimeric liver mouse model, which was capable of supporting HBV infection in vivo and evaluating the effects of antiviral drugs. Our results shed light into improving the cellular and animal models for studying HBV and other hepatotropic viruses.
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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
影响因子：
7.6
作者：
Cai, Dawei;Wang, Xiaohe;Yan, Ran;Mao, Richeng;Liu, Yuanjie;Ji, Changhua;Cuconati, Andrea;Guo, Haitao
通讯作者：
Guo, Haitao
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：
GUIDOTTI, LG;MATZKE, B;CHISARI, FV
通讯作者：
CHISARI, FV