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

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

Research output: Contribution to journalArticle

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 urokinasetype 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.

Original languageEnglish (US)
Pages (from-to)4953-4964
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number11
DOIs
StatePublished - Nov 3 2014
Externally publishedYes

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Hepatovirus
Hepacivirus
Hepatocytes
Stem Cells
Virus Diseases
Induced Pluripotent Stem Cells
Regenerative Medicine
Plasminogen Activators
Liver
Chronic Hepatitis C
Infection
Interferons
Transgenic Mice
Antiviral Agents
Liver Diseases
Genotype
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Carpentier, A., Tesfaye, A., Chu, V., Nimgaonkar, I., Zhang, F., Lee, S. B., ... Liang, T. J. (2014). Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model. Journal of Clinical Investigation, 124(11), 4953-4964. https://doi.org/10.1172/JCI75456

Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model. / Carpentier, Arnaud; Tesfaye, Abeba; Chu, Virginia; Nimgaonkar, Ila; Zhang, Fang; Lee, Seung Bum; Thorgeirsson, Snorri S.; Feinstone, Stephen M.; Liang, T. Jake.

In: Journal of Clinical Investigation, Vol. 124, No. 11, 03.11.2014, p. 4953-4964.

Research output: Contribution to journalArticle

Carpentier, A, Tesfaye, A, Chu, V, Nimgaonkar, I, Zhang, F, Lee, SB, Thorgeirsson, SS, Feinstone, SM & Liang, TJ 2014, 'Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model', Journal of Clinical Investigation, vol. 124, no. 11, pp. 4953-4964. https://doi.org/10.1172/JCI75456
Carpentier A, Tesfaye A, Chu V, Nimgaonkar I, Zhang F, Lee SB et al. Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model. Journal of Clinical Investigation. 2014 Nov 3;124(11):4953-4964. https://doi.org/10.1172/JCI75456
Carpentier, Arnaud ; Tesfaye, Abeba ; Chu, Virginia ; Nimgaonkar, Ila ; Zhang, Fang ; Lee, Seung Bum ; Thorgeirsson, Snorri S. ; Feinstone, Stephen M. ; Liang, T. Jake. / Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 11. pp. 4953-4964.
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