从人诱导的多能干细胞重演肝脏类器官中的乙型肝炎病毒 -

StephenW

EBioMedicine. 2018 Aug 14. pii: S2352-3964(18)30300-1. doi: 10.1016/j.ebiom.2018.08.014. [Epub ahead of print]
Recapitulation of hepatitis B virus-host interactions in liver organoids from human induced pluripotent stem cells.
Nie YZ1, Zheng YW2, Miyakawa K3, Murata S1, Zhang RR1, Sekine K1, Ueno Y1, Takebe T1, Wakita T4, Ryo A3, Taniguchi H5.
Author information

1
    Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
2
    Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Department of Advanced Gastroenterological Surgical Science and Technology, University of Tsukuba, Tsukuba-shi, Ibaraki 305-8575, Japan; Research Center of Stem Cells and Regenerative Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China,. Electronic address: [email protected].
3
    Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
4
    Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, 162-8640 Tokyo, Japan.
5
    Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan. Electronic address: [email protected].

Abstract

Therapies against hepatitis B virus (HBV) have improved in recent decades; however, the development of individualized treatments has been limited by the lack of individualized infection models. In this study, we used human induced pluripotent stem cell (hiPSC) to generate a functional liver organoid (LO) that inherited the genetic background of the donor, and evaluated its application in modeling HBV infection and exploring virus-host interactions. To establish a functional hiPSC-LO, we cultured hiPSC-derived endodermal, mesenchymal, and endothelial cells with a chemically defined medium in a three-dimensional microwell culture system. Based on cell-cell interactions, these cells could organize themselves and gradually differentiate into a functional organoid, which exhibited stronger hepatic functions than hiPSC derived hepatic like cell (HLC). Moreover, the functional LO demonstrated more susceptibility to HBV infection than hiPSC-HLC, and could maintain HBV propagation and produce infectious virus for a prolonged duration. Furthermore, we found that virus infection could cause hepatic dysfunction of hiPSC-LOs, with down-regulation of hepatic gene expression, induced release of early acute liver failure markers, and altered hepatic ultrastructure. Therefore, our study demonstrated that HBV infection in hiPSC-LOs could recapitulate virus life cycle and virus induced hepatic dysfunction, suggesting that hiPSC-LOs may provide a promising individualized infection model for the development of individualized treatment for hepatitis.
KEYWORDS:

Hepatitis B virus; Liver organoid; Virus-host interactions; hiPSC

PMID:
    30120080
DOI:
    10.1016/j.ebiom.2018.08.014

StephenW

EBioMedicine。 2018年8月14日.pii：S2352-3964（18）30300-1。 doi：10.1016 / j.ebiom.2018.08.014。 [提前打印]
从人诱导的多能干细胞重演肝脏类器官中的乙型肝炎病毒 - 宿主相互作用。
Nie YZ1，Zheng YW2，Miyakawa K3，Murata S1，Zhang RR1，Sekine K1，Ueno Y1，Takebe T1，Wakita T4，Ryo A3，Taniguchi H5。
作者信息

1
    横滨市立大学医学研究科再生医学系，横滨，神奈川县236-0004，日本。
2
    横滨市立大学医学研究科再生医学系，日本神奈川县横滨市236-0004;日本茨城县筑波市筑波大学先进胃肠外科科学技术系，305-8575;江苏大学附属医院干细胞与再生医学研究中心，江苏镇江212001电子地址：[email protected]。
3
    横滨市立大学医学研究科微生物学系，横滨，神奈川县236-0004，日本。
4
    国立传染病研究所病毒学系，新宿区富山1-23-1，162-8640东京，日本。
五
    横滨市立大学医学研究科再生医学系，日本神奈川县横滨市236-0004;横滨市立大学医学研究科高级医学研究中心，日本神奈川县横滨市236-0004。电子地址：[email protected]。

抽象

近几十年来，针对乙型肝炎病毒（HBV）的治疗方法有所改善;然而，由于缺乏个体化的感染模型，个体化治疗的发展受到限制。在这项研究中，我们使用人类诱导的多能干细胞（hiPSC）产生功能性肝脏器官（LO），遗传了供体的遗传背景，并评估其在HBV感染建模和探索病毒 - 宿主相互作用中的应用。为了建立功能性hiPSC-LO，我们在三维微孔培养系统中用化学成分确定的培养基培养hiPSC衍生的内胚层，间充质和内皮细胞。基于细胞 - 细胞相互作用，这些细胞可以自我组织并逐渐分化成功能性类器官，其表现出比hiPSC衍生的肝样细胞（HLC）更强的肝功能。此外，功能性LO表现出比hiPSC-HLC更易感染HBV感染，并且可以维持HBV传播并长时间产生感染性病毒。此外，我们发现病毒感染可引起hiPSC-LOs的肝功能障碍，肝基因表达下调，诱导早期急性肝衰竭标志物释放和肝脏超微结构改变。因此，我们的研究表明，hiPSC-LOs中的HBV感染可以重现病毒生命周期和病毒诱导的肝功能障碍，这表明hiPSC-LOs可以为个体化肝炎治疗的发展提供有希望的个体化感染模型。
关键词：

乙型肝炎病毒;肝脏类器官;病毒 - 宿主相互作用;的hiPSC

结论：
    30120080
DOI：
    10.1016 / j.ebiom.2018.08.014