Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma
| Autor: | Tokameh Mahmoudi, Monique M.A. Verstegen, Tanvir Hossain, Pantelis Hatzis, Robert P. de Vries, Jan Nm IJzermans, Mir M. Khalid, Elisa De Crignis, Shahla Romal, Tsung Wai Kan, Helmuth Gehart, Christina Koutsothanassis, Luc J. W. van der Laan, Shringar Rao, Meritxell Huch, Farzin Pourfarzad, Robert-Jan Palstra, Sylvia F. Boj, Charles A. Boucher, Panagiotis Moulos, Ameneh Bazrafshan, Fabrizia Carofiglio, Hans Clevers |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research, Biochemistry, Surgery, Virology, Pathology, Urology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.disease_cause
Recombinant virus Virus Replication 0302 clinical medicine Models Living Donors Biology (General) Microbiology and Infectious Disease 0303 health sciences Hepatocellular/virology General Neuroscience Hepatitis B virus/pathogenicity Liver Neoplasms Carcinoma Hepatocellular/virology virus diseases General Medicine cccDNA Hep G2 Cells hepatocellular carcinoma Hepatitis B 3. Good health Liver Neoplasms/virology Organoids Liver HBeAg 030220 oncology & carcinogenesis Hepatocellular carcinoma Medicine Liver/pathology Research Article Human Hepatitis B virus Carcinoma Hepatocellular QH301-705.5 Science Biology Models Biological General Biochemistry Genetics and Molecular Biology 03 medical and health sciences SDG 3 - Good Health and Well-being medicine Organoid Humans 030304 developmental biology liver organoids General Immunology and Microbiology Carcinoma Organoids/virology Hepatitis B/complications Biological medicine.disease digestive system diseases Cancer research Carcinogenesis Ex vivo |
| Zdroj: | eLife, Vol 10 (2021) eLife, 10. eLife Sciences Publications eLife, 10 eLife |
| ISSN: | 2050-084X |
| Popis: | 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. eLife, 10 ISSN:2050-084X |
| Databáze: | OpenAIRE |
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