Hepatitis C virus infects and perturbs liver stem cells

NL Meyers, T Ashuach, DE Lyons, MM Khalid, CR Simoneau, AL Erickson, M Bouhaddou, TT Nguyen, GR Kumar, TY Taha, V Natarajan, JL Baron, N Neff, F Zanini, T Mahmoudi, SR Quake, NJ Krogan, S Cooper, TC Mcdevitt, N Yosef*M Ott*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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Abstract

Hepatitis C virus (HCV) is the leading cause of death from liver disease. How HCV infection causes lasting liver damage and increases cancer risk remains unclear. Here, we identify bipotent liver stem cells as novel targets for HCV infection, and their erroneous differentiation as the potential cause of impaired liver regeneration and cancer development. We show 3D organoids generated from liver stem cells from actively HCV-infected individuals carry replicating virus and maintain low-grade infection over months. Organoids can be infected with a primary HCV isolate. Virus-inclusive single-cell RNA sequencing uncovered transcriptional reprogramming in HCV+ cells supporting hepatocytic differentiation, cancer stem cell development, and viral replication while stem cell proliferation and interferon signaling are disrupted. Our data add a new pathogenesis mechanism—infection of liver stem cells—to the biology of HCV infection that may explain progressive liver damage and enhanced cancer risk through an altered stem cell state.
Original languageEnglish
Article number0131823
Number of pages21
JournalmBio
Volume14
Issue number6
Early online date8 Nov 2023
DOIs
Publication statusPublished - Dec 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 Meyers et al.

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