Hepatitis C virus infects and perturbs liver stem cells

Nathan L Meyers; Tal Ashuach; Danielle E Lyons; Mir M Khalid; Camille R Simoneau; Ann L Erickson; Mehdi Bouhaddou; Thong T Nguyen; G Renuka Kumar; Taha Y Taha; Vaishaali Natarajan; Jody L Baron; Norma Neff; Fabio Zanini; Tokameh Mahmoudi; Stephen R Quake; Nevan J Krogan; Stewart Cooper; Todd C McDevitt; Nir Yosef; Melanie Ott

doi:10.1128/mbio.01318-23

Hepatitis C virus infects and perturbs liver stem cells

mBio. 2023 Dec 19;14(6):e0131823. doi: 10.1128/mbio.01318-23. Epub 2023 Nov 8.

Authors

Nathan L Meyers¹, Tal Ashuach^#², Danielle E Lyons^#¹, Mir M Khalid^#¹, Camille R Simoneau¹, Ann L Erickson³, Mehdi Bouhaddou^{4

5

6}, Thong T Nguyen¹, G Renuka Kumar¹, Taha Y Taha¹, Vaishaali Natarajan⁷, Jody L Baron⁸, Norma Neff⁹, Fabio Zanini¹⁰, Tokameh Mahmoudi¹¹, Stephen R Quake^{9

10}, Nevan J Krogan^{4

5

6}, Stewart Cooper³, Todd C McDevitt^{7

12}, Nir Yosef^{2

13}, Melanie Ott^{1

8

9}

Affiliations

¹ Gladstone Institute of Virology, San Francisco, California, USA.
² Department of Electrical Engineering and Computer Science and Center for Computational Biology, University of California Berkeley, Berkeley, California, USA.
³ California Pacific Medical Center Research Institute, San Francisco, California, USA.
⁴ Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA.
⁵ Gladstone Institute of Data Science and Biotechnology, San Francisco, California, USA.
⁶ Quantitative Biosciences Institute, University of California, San Francisco, California, USA.
⁷ Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
⁸ Department of Medicine, University of California San Francisco, San Francisco, California, USA.
⁹ Chan Zuckerburg Biohub, San Francisco, California, USA.
¹⁰ Department of Bioengineering, Stanford University, Stanford, California, USA.
¹¹ Department of Biochemistry, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹² Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
¹³ Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachusetts, USA.

^# Contributed equally.

Abstract

The hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease. Here, we show that HCV maintains low-grade infections in liver organoids for the first time. HCV infection in liver organoids leads to transcriptional reprogramming causing cancer cell development and altered immune response. Our finding shows how HCV infection in liver organoids mimics HCV infection and patient pathogenesis. These results reveal that HCV infection in liver organoids contributes to liver disease progression.

Keywords: chronic infection; hepatitis c virus; hepatocellular carcinoma; liver disease; organoid; single-cell RNA sequencing; stem cell.

MeSH terms

Animals
Hepacivirus* / genetics
Hepacivirus* / physiology
Hepatitis C* / virology
Hepatocytes / virology
Humans
Liver* / virology
Mice
Organoids* / virology
Stem Cells / virology

Abstract

MeSH terms

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