Human-induced pluripotent stem cell-derived hepatocyte platform in modeling of SARS-CoV-2 infection

IF 1.7 Q3 GASTROENTEROLOGY & HEPATOLOGY JGH Open Pub Date : 2024-07-12 DOI:10.1002/jgh3.13039

Ruiqi Zhang, Rui Wei, Yangyang Yuan, Na Li, Yang Hu, Kwok-Hung Chan, Ivan Fan-Ngai Hung, Hung-Fat Tse

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Abstract

Background and Aim

Currently, SARS-CoV-2 is still spreading rapidly and globally. A large proportion of patients with COVID-19 developed liver injuries. The human-induced pluripotent stem cell (iPSC)-derived hepatocytes recapitulate primary human hepatocytes and have been widely used in studies of liver diseases.

Methods

To explore the susceptibility of hepatocytes to SARS-CoV-2, we differentiated iPSCs to functional hepatocytes and tried infecting them with different MOI (1, 0.1, 0.01) of SARS-CoV-2.

Results

The iPSC-derived hepatocytes are highly susceptible to virus infection, even at 0.01 MOI. Other than the ancestral strain, iHeps also support the replication of SARS-CoV-2 variants including alpha, beta, theta, and delta. More interestingly, the ACE2 expression significantly upregulated after infection, suggesting a vicious cycle between virus infection and liver injury.

Conclusions

The iPSC-derived hepatocytes can support the replication of SARS-CoV-2, and this platform could be used to investigate the SARS-CoV-2 hepatotropism and hepatic pathogenic mechanisms.

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人诱导多能干细胞衍生肝细胞平台在 SARS-CoV-2 感染建模中的应用

背景和目的目前，SARS-CoV-2 仍在全球范围内迅速蔓延。大部分 COVID-19 患者都出现了肝损伤。人类诱导多能干细胞（iPSC）衍生的肝细胞可再现原代人类肝细胞，已被广泛用于肝脏疾病的研究。方法为了探索肝细胞对 SARS-CoV-2 的易感性，我们将 iPSC 分化为功能性肝细胞，并尝试用不同 MOI（1、0.1、0.01）的 SARS-CoV-2 感染它们。结果 iPSC 衍生的肝细胞对病毒感染高度敏感，即使在 0.01 MOI 时也是如此。除祖先毒株外，iHeps 还支持 SARS-CoV-2 变体（包括 alpha、beta、theta 和 delta）的复制。更有趣的是，感染后 ACE2 的表达明显上调，这表明病毒感染和肝损伤之间存在恶性循环。结论 iPSC 衍生的肝细胞可支持 SARS-CoV-2 的复制，这一平台可用于研究 SARS-CoV-2 的趋肝性和肝脏致病机制。

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