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人多能干细胞来源的肝细胞用于乙型和丁型肝炎病毒感染模型的建立。

An hepatitis B and D virus infection model using human pluripotent stem cell-derived hepatocytes.

机构信息

Schaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany.

German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany.

出版信息

EMBO Rep. 2024 Oct;25(10):4311-4336. doi: 10.1038/s44319-024-00236-0. Epub 2024 Sep 4.

DOI:10.1038/s44319-024-00236-0
PMID:39232200
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11466959/
Abstract

Current culture systems available for studying hepatitis D virus (HDV) are suboptimal. In this study, we demonstrate that hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) are fully permissive to HDV infection across various tested genotypes. When co-infected with the helper hepatitis B virus (HBV) or transduced to express the HBV envelope protein HBsAg, HLCs effectively release infectious progeny virions. We also show that HBsAg-expressing HLCs support the extracellular spread of HDV, thus providing a valuable platform for testing available anti-HDV regimens. By challenging the cells along the differentiation with HDV infection, we have identified CD63 as a potential HDV co-entry factor that was rate-limiting for HDV infection in immature hepatocytes. Given their renewable source and the potential to derive hPSCs from individual patients, we propose HLCs as a promising model for investigating HDV biology. Our findings offer new insights into HDV infection and expand the repertoire of research tools available for the development of therapeutic interventions.

摘要

目前用于研究丁型肝炎病毒（HDV）的培养体系并不理想。在这项研究中，我们证明了源自人类多能干细胞（hPSC）的肝样细胞（HLC）可被各种测试基因型的 HDV 完全感染。当与辅助性乙型肝炎病毒（HBV）共感染或转导表达 HBV 包膜蛋白 HBsAg 时，HLC 可有效释放感染性的病毒粒子。我们还表明，表达 HBsAg 的 HLC 支持 HDV 的细胞外传播，从而为测试现有抗 HDV 方案提供了有价值的平台。通过用 HDV 感染对细胞沿分化路径进行挑战，我们发现 CD63 是一种潜在的 HDV 共同进入因子，它对未成熟肝细胞中的 HDV 感染起限速作用。鉴于其可再生来源以及能够从个体患者中获得 hPSC，我们提出 HLC 是研究 HDV 生物学的有前途的模型。我们的研究结果为 HDV 感染提供了新的见解，并扩展了用于开发治疗干预措施的研究工具库。

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