Engrafted human stem cell–derived hepatocytes establish an infectious HCV murine model
Arnaud Carpentier, … , Stephen M. Feinstone, T. Jake Liang
Arnaud Carpentier, … , Stephen M. Feinstone, T. Jake Liang
Published October 8, 2014
Citation Information: J Clin Invest. 2014;124(11):4953-4964. https://doi.org/10.1172/JCI75456.
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Technical Advance Hepatology

Engrafted human stem cell–derived hepatocytes establish an infectious HCV murine model

Abstract

The demonstrated ability to differentiate both human embryonic stem cells (hESCs) and patient-derived induced pluripotent stem cells (hiPSCs) into hepatocyte-like cells (HLCs) holds great promise for both regenerative medicine and liver disease research. Here, we determined that, despite an immature phenotype, differentiated HLCs are permissive to hepatitis C virus (HCV) infection and mount an interferon response to HCV infection in vitro. HLCs differentiated from hESCs and hiPSCs could be engrafted in the liver parenchyma of immune-deficient transgenic mice carrying the urokinase-type plasminogen activator gene driven by the major urinary protein promoter. The HLCs were maintained for more than 3 months in the livers of chimeric mice, in which they underwent further maturation and proliferation. These engrafted and expanded human HLCs were permissive to in vivo infection with HCV-positive sera and supported long-term infection of multiple HCV genotypes. Our study demonstrates efficient engraftment and in vivo HCV infection of human stem cell–derived hepatocytes and provides a model to study chronic HCV infection in patient-derived hepatocytes, action of antiviral therapies, and the biology of HCV infection.

Authors

Arnaud Carpentier, Abeba Tesfaye, Virginia Chu, Ila Nimgaonkar, Fang Zhang, Seung Bum Lee, Snorri S. Thorgeirsson, Stephen M. Feinstone, T. Jake Liang

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Figure 7

HCV infection of engrafted HLCs.

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HCV infection of engrafted HLCs. Two weeks pe, chimeric mice were inocul...
Two weeks pe, chimeric mice were inoculated with HCV+ plasma of genotype 1a, 1b, or 3a. (A and B) HCV RNA quantified by RTqPCR, 1, 2, and 3 months after inoculation, in the sera of mice inoculated with (A) diluted chimpanzee sera containing 30 (black) or 1,000 (blue) CID50 HCV of genotype 1a (strain HC-TN) or with (B) chimpanzee sera of HCV of genotype 1b (strain CG1B) (blue) or genotype 3a (strain S52) (black) (100 CID50). Control noninoculated engrafted mice are depicted in red. Individual lines represent individual mice. (C) HCV core antigen assessed by ELISA in the sera of the mice 3 months after inoculation. Horizontal bars indicate the mean. Non inf, noninfected. (D) Correlation between HCV RNA titers and HCV core antigen concentrations in the sera of mice 3 months pe.