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人诱导多能干细胞来源的肝细胞样细胞作为乙型肝炎病毒感染的体外模型。

Human induced-pluripotent stem cell-derived hepatocyte-like cells as an in vitro model of human hepatitis B virus infection.

机构信息

Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Laboratory of Regulatory Sciences for Oligonucleotide Therapeutics, Clinical Drug Development Unit, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

出版信息

Sci Rep. 2017 Apr 4;7:45698. doi: 10.1038/srep45698.

DOI:10.1038/srep45698
PMID:28374759
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5379564/
Abstract

In order to understand the life cycle of hepatitis B virus (HBV) and to develop efficient anti-HBV drugs, a useful in vitro cell culture system which allows HBV infection and recapitulates virus-host interactions is essential; however, pre-existing in vitro HBV infection models are often problematic. Here, we examined the potential of human induced-pluripotent stem (iPS) cell-derived hepatocyte-like cells (iPS-HLCs) as an in vitro HBV infection model. Expression levels of several genes involved in HBV infection, including the sodium taurocholate cotransporting polypeptide (NTCP) gene, were gradually elevated as the differentiation status of human iPS cells proceeded to iPS-HLCs. The mRNA levels of these genes were comparable between primary human hepatocytes (PHHs) and iPS-HLCs. Following inoculation with HBV, we found significant production of HBV proteins and viral RNAs in iPS-HLCs. The three major forms of the HBV genome were detected in iPS-HLCs by Southern blotting analysis. Anti-HBV agents entecavir and Myrcludex-B, which are a nucleoside analogue reverse transcriptase inhibitor and a synthetic pre-S1 peptide, respectively, significantly inhibited HBV infection in iPS-HLCs. These data demonstrate that iPS-HLCs can be used as a promising in vitro HBV infection model.

摘要

为了了解乙型肝炎病毒 (HBV) 的生命周期并开发有效的抗 HBV 药物，需要建立一种能够允许 HBV 感染并再现病毒-宿主相互作用的有用的体外细胞培养系统；然而，现有的体外 HBV 感染模型往往存在问题。在这里，我们研究了人诱导多能干细胞 (iPS) 细胞衍生的肝样细胞 (iPS-HLC) 作为体外 HBV 感染模型的潜力。参与 HBV 感染的几个基因的表达水平，包括牛磺胆酸钠共转运多肽 (NTCP) 基因，随着人 iPS 细胞向 iPS-HLC 的分化状态逐渐升高。这些基因的 mRNA 水平在原代人肝细胞 (PHH) 和 iPS-HLC 之间相当。在接种 HBV 后，我们发现 iPS-HLC 中 HBV 蛋白和病毒 RNA 的大量产生。Southern 印迹分析检测到 iPS-HLC 中存在 HBV 基因组的三种主要形式。核苷类似物逆转录酶抑制剂恩替卡韦和合成前 S1 肽 Myrcludex-B 等抗 HBV 药物显著抑制了 iPS-HLC 中的 HBV 感染。这些数据表明 iPS-HLC 可作为一种有前途的体外 HBV 感染模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/8050fe4965c9/srep45698-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/39f5f7f7083d/srep45698-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/a3ceab3ba836/srep45698-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/d74845bde21d/srep45698-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/8050fe4965c9/srep45698-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/39f5f7f7083d/srep45698-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/a3ceab3ba836/srep45698-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/d74845bde21d/srep45698-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c97/5379564/8050fe4965c9/srep45698-f4.jpg

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