Hepatitis C Virus Infects and Perturbs Liver Stem Cells

Abstract

SummaryHepatitis C virus (HCV) is the leading cause of death from liver disease. How HCV infection causes lasting liver damage and increases cancer risk beyond viral clearance remains unclear. 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 extensive 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 adds a pathogenesis factor – infection of liver stem cells – to the biology of HCV infection that explains persistent liver damage and enhanced cancer risk through an altered stem cell state.

3D Human Organoids: The Next “Viral” Model for the Molecular Basis of Infectious Diseases

“…Using hepatoma organoids, a study showed that the hepatitis C virus (HCV) uses entry factors such as scavenger receptor BI (SR-B1), epidermal growth factor receptor (EGFR), cluster of differentiation 81 (CD81), claudin-1 (CLDN1) and occludin (OCLN) in a sequential actin-dependent manner, to facilitate entry into the organoid system [ 71 ]. Recently, organoids generated from liver stem cells of HCV-infected individuals showed viral replication and sustained a low-grade infection for months [ 72 ]. Moreover, single-cell RNA sequencing performed during the same study demonstrated that infected cells showed extensive transcriptional reprogramming, whereby cancer stem cell development, viral replication and hepatocyte differentiation were promoted, whereas IFN signalling and proliferation were antagonised [ 72 ].…”

“…Recently, organoids generated from liver stem cells of HCV-infected individuals showed viral replication and sustained a low-grade infection for months [ 72 ]. Moreover, single-cell RNA sequencing performed during the same study demonstrated that infected cells showed extensive transcriptional reprogramming, whereby cancer stem cell development, viral replication and hepatocyte differentiation were promoted, whereas IFN signalling and proliferation were antagonised [ 72 ]. Thus, this has shone light on how HCV infection might cause sustained liver damage and increase the risk of cancer in chronically infected patients [ 72 ].…”

“…Moreover, single-cell RNA sequencing performed during the same study demonstrated that infected cells showed extensive transcriptional reprogramming, whereby cancer stem cell development, viral replication and hepatocyte differentiation were promoted, whereas IFN signalling and proliferation were antagonised [ 72 ]. Thus, this has shone light on how HCV infection might cause sustained liver damage and increase the risk of cancer in chronically infected patients [ 72 ]. Lately, liver organoids were also utilised to model hepatitis B virus (HBV) infection and these functional organoids were more susceptible to infection as compared to iPSC-derived hepatocyte-like cells [ 68 ].…”

“…Baktash, et al[71],Meyers, et al[72] Arez, et al[73],Mo and McGugan[74] Mills, et al[75],Xie, et al[76] …”