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 YosefMelanie Ott

Research output: Contribution to journalArticlepeer-review


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
Issue number6
StatePublished - Dec 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Virology


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