Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma

Elisa De Crignis, Tanvir Hossain, Shahla Romal, Fabrizia Carofiglio, Panagiotis Moulos, Mir Mubashir Khalid, Shringar Rao, Ameneh Bazrafshan, Monique Ma Verstegen, Farzin Pourfarzad, Christina Koutsothanassis, Helmuth Gehart, Tsung Wai Kan, Robert-Jan Palstra, Charles Boucher, Jan Nm IJzermans, Meritxell Huch, Sylvia F Boj, Robert Vries, Hans CleversLuc Jw van der Laan, Pantelis Hatzis, Tokameh Mahmoudi

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

56 Citaten (Scopus)

Samenvatting

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 covalently closed circular DNA (cccDNA) and HBV early antigen (HBeAg), 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 and drug-induced toxicity. We also studied HBV replication in transgenically modified organoids; liver organoids exogenously overexpressing the HBV receptor sodium taurocholate co-transporting polypeptide (NTCP) after 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 hepatocellular carcinoma (HCC) cohort on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset and away from healthy liver tissue, and may provide invaluable novel biomarkers for the development of HCC and surveillance in HBV-infected patients.

Originele taal-2Engels
TijdschrifteLife
Volume10
DOI's
StatusGepubliceerd - 30 jul. 2021

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