Modeling Dengue Virus-Hepatic Cell Interactions Using Human Pluripotent Stem Cell-Derived Hepatocyte-like Cells.
Modeling Dengue Virus-Hepatic Cell Interactions Using Human Pluripotent Stem Cell-Derived Hepatocyte-like Cells.
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DOI：
10.1016/j.stemcr.2016.07.012
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发表时间：
2016-09-13
影响因子：
5.9
通讯作者：
Tang, Hengli
中科院分区：
文献类型：
--
作者：
Lang, Jianshe;Vera, Daniel;Cheng, Yichen;Tang, Hengli
由于对登革病毒（DENV）感染和病理的分子机制了解不完全，部分原因是能够捕捉登革病毒引起的全面细胞变化的合适细胞培养或动物模型有限，因此阻碍了登革热抗病毒药物和疫苗的开发。在本研究中，我们将人多能干细胞（human pluripotent stem cells, hPSCs）分化为DENV的靶细胞之一肝细胞，探讨DENV-肝细胞相互作用的各个方面。hpsc衍生的肝细胞样细胞（HLCs）支持持续性和生产性DENV感染。DENV激活干扰素通路可保护旁观者细胞免受感染，并保护感染细胞免于大量凋亡。此外，DENV感染激活了NF-κB通路，导致促炎细胞因子的产生，并下调许多肝脏特异性基因，如白蛋白和凝血因子v。我们的研究证明了hpsc来源的肝细胞作为DENV感染的体外模型的实用性，并揭示了DENV-宿主相互作用的重要方面。来自人乳头状细胞的肝细胞样细胞（hlc）支持DENV感染，DENV感染的hlc导致与病理相关的细胞反应，hlc代表了一个新的模型系统来研究登革病毒感染的肝脏感染/疾病模型，模拟由DENV感染引起的全面细胞变化是有限的。在这里，Tang和他的同事使用多能干细胞来产生一个可再生的细胞模型，该模型捕获了与登革热发病机制相关的体外表型。结合靶向分化和病毒感染为研究宿主遗传与登革热感染及其发病机制的界面提供了一种新的模式。
The development of dengue antivirals and vaccine has been hampered by the incomplete understanding of molecular mechanisms of dengue virus (DENV) infection and pathology, partly due to the limited suitable cell culture or animal models that can capture the comprehensive cellular changes induced by DENV. In this study, we differentiated human pluripotent stem cells (hPSCs) into hepatocytes, one of the target cells of DENV, to investigate various aspects of DENV-hepatocyte interaction. hPSC-derived hepatocyte-like cells (HLCs) supported persistent and productive DENV infection. The activation of interferon pathways by DENV protected bystander cells from infection and protected the infected cells from massive apoptosis. Furthermore, DENV infection activated the NF-κB pathway, which led to production of proinflammatory cytokines and downregulated many liver-specific genes such as albumin and coagulation factor V. Our study demonstrates the utility of hPSC-derived hepatocytes as an in vitro model for DENV infection and reveals important aspects of DENV-host interactions. Hepatocyte-like cells (HLCs) derived from hPSCs support productive DENV infection DENV infection of HLCs leads to cellular responses that are relevant to pathology HLCs represent a new model system to study dengue virus infection of liver Infection/disease models modeling the comprehensive cellular changes induced by DENV infection are limited. Here, Tang and colleagues use pluripotent stem cells to produce a renewable cell model that captures in vitro phenotypes relevant for dengue pathogenesis. Combining targeted differentiation and viral infection represents a new model to study the interface of host genetics and dengue infection and pathogenesis.
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