RT Journal Article
SR Electronic
T1 Human liver organoids; a patient-derived primary model for HBV Infection and Related Hepatocellular Carcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 568147
DO 10.1101/568147
A1 Elisa De Crignis
A1 Shahla Romal
A1 Fabrizia Carofiglio
A1 Panagiotis Moulos
A1 Monique M.A. Verstegen
A1 Mir Mubashir Khalid
A1 Farzin Pourfarzad
A1 Shringar Rao
A1 Ameneh Bazrafshan
A1 Christina Koutsothanassis
A1 Helmuth Gehart
A1 Tsung Wai Kan
A1 Robert-Jan Palstra
A1 Charles Boucher
A1 Jan M.N. IJzermans
A1 Meritxell Huch
A1 Sylvia F. Boj
A1 Robert Vries
A1 Hans Clevers
A1 Luc van der Laan
A1 Pantelis Hatzis
A1 Tokameh Mahmoudi
YR 2020
UL http://biorxiv.org/content/early/2020/11/11/568147.abstract
AB The molecular events that drive Hepatitis B virus (HBV)-mediated transformation and tumorigenesis have remained largely unclear, due to the absence of a relevant primary model system. Here we propose the use of human liver organoids as a platform for modeling HBV infection and related tumorigenesis. We first describe a primary ex vivo HBV-infection model derived from healthy donor liver organoids after challenge with recombinant virus or HBV-infected patient serum. HBV infected organoids produced cccDNA, expressed intracellular HBV RNA and proteins, and produced infectious HBV. This ex vivo HBV infected primary differentiated hepatocyte organoid platform was amenable to drug screening for both anti-HBV activity as well as for drug-induced toxicity. We also studied HBV replication in transgenically modified organoids; liver organoids exogenously overexpressing the HBV receptor NTCP by lentiviral transduction were not more susceptible to HBV, suggesting the necessity for additional host factors for efficient infection. We also generated transgenic organoids harboring integrated HBV, representing a long-term culture system also suitable for viral production and the study of HBV transcription. Finally, we generated HBV-infected patient-derived liver organoids from non-tumor cirrhotic tissue of explants from liver transplant patients. Interestingly, transcriptomic analysis of patient-derived liver organoids indicated the presence of an aberrant early cancer gene signature, which clustered with the HCC cohort on the TCGA LIHC dataset and away from healthy liver tissue, and may provide invaluable novel biomarkers for disease surveillance and development of HCC in HBV infected patients.Competing Interest StatementThe authors have declared no competing interest.