Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma.
Hepatitis B virus
hepatocellular carcinoma
human
infectious disease
liver organoids
microbiology
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
30 07 2021
30 07 2021
Historique:
received:
25
08
2020
accepted:
29
07
2021
pubmed:
31
7
2021
medline:
15
10
2021
entrez:
30
7
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34328417
doi: 10.7554/eLife.60747
pii: 60747
pmc: PMC8384419
doi:
pii:
Banques de données
GEO
['GSE126798']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021, De Crignis et al.
Déclaration de conflit d'intérêts
ED, TH, SR, FC, PM, MK, SR, AB, MV, FP, CK, HG, TK, RP, CB, JI, MH, SB, RV, HC, Lv, PH, TM No competing interests declared
Références
Nucleic Acids Res. 2012 Jan;40(1):148-58
pubmed: 21914722
Nat Rev Gastroenterol Hepatol. 2016 Jun;13(6):362-74
pubmed: 27075261
Curr Genomics. 2014 Dec;15(6):469-80
pubmed: 25646075
Cell. 2017 Jun 15;169(7):1327-1341.e23
pubmed: 28622513
Elife. 2012 Nov 13;1:e00049
pubmed: 23150796
Sci Rep. 2017 Apr 04;7:45698
pubmed: 28374759
Nat Genet. 2012 Oct;44(10):1117-21
pubmed: 22922871
J Virol. 1996 Jul;70(7):4567-75
pubmed: 8676483
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Gastroenterology. 2019 Jan;156(2):338-354
pubmed: 30243619
Nat Genet. 2012 May 27;44(7):765-9
pubmed: 22634754
Hepatology. 2011 Sep 2;54(3):829-36
pubmed: 21809355
Carcinogenesis. 2008 Oct;29(10):1901-10
pubmed: 18632756
Nature. 2013 Feb 14;494(7436):247-50
pubmed: 23354049
Stem Cells Transl Med. 2016 Mar;5(3):325-30
pubmed: 26798060
N Engl J Med. 1995 Oct 26;333(17):1099-105
pubmed: 7565947
Cell. 2015 Jan 15;160(1-2):299-312
pubmed: 25533785
Nat Protoc. 2015 Dec;10(12):2027-53
pubmed: 26584444
J Virol. 1988 Aug;62(8):2836-44
pubmed: 2839705
Cold Spring Harb Perspect Med. 2015 May 01;5(5):a021410
pubmed: 25934461
Nat Rev Gastroenterol Hepatol. 2014 Jun;11(6):340-9
pubmed: 24473361
Genome Res. 2012 Apr;22(4):593-601
pubmed: 22267523
J Cancer Res Clin Oncol. 2015 Aug;141(8):1333-41
pubmed: 25230901
Cancer Res. 2016 Nov 1;76(21):6374-6381
pubmed: 27634755
Elife. 2021 Jul 30;10:
pubmed: 34328417
Hepatology. 2009 May;49(5 Suppl):S56-60
pubmed: 19399807
Nat Commun. 2017 Jul 25;8(1):125
pubmed: 28743900
Nucleic Acids Res. 2012 Jul;40(Web Server issue):W478-83
pubmed: 22573175
Cells. 2019 Nov 24;8(12):
pubmed: 31771261
EBioMedicine. 2018 Sep;35:114-123
pubmed: 30120080
Cancer Biol Med. 2014 Sep;11(3):182-90
pubmed: 25364579
BMC Cancer. 2019 Jul 18;19(1):707
pubmed: 31319796
Nat Commun. 2016 Oct 05;7:12992
pubmed: 27703150
Gastroenterology. 2012 May;142(6):1264-1273.e1
pubmed: 22537432
Nat Protoc. 2008;3(6):1101-8
pubmed: 18546601
Int J Mol Sci. 2016 Jun 14;17(6):
pubmed: 27314335
J Cell Physiol. 2019 Apr;234(4):3555-3569
pubmed: 30565670
J Hepatol. 2017 Mar;66(3):494-503
pubmed: 27746336
Nat Rev Gastroenterol Hepatol. 2017 Jun;14(6):327-328
pubmed: 28400622
Sci Rep. 2016 Jul 08;6:29358
pubmed: 27386799
Nucleic Acids Res. 2015 Feb 27;43(4):e25
pubmed: 25452340
J Hepatol. 2008 Feb;48(2):335-52
pubmed: 18096267
Biochem Biophys Res Commun. 2014 Jan 17;443(3):808-13
pubmed: 24342612
Nat Genet. 2012 May 27;44(7):760-4
pubmed: 22634756
Genome Res. 2012 Oct;22(10):2008-17
pubmed: 22722343
Front Genet. 2018 Jul 19;9:261
pubmed: 30073017
Genome Biol. 2013 Apr 25;14(4):R36
pubmed: 23618408
Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):12193-8
pubmed: 25092305
PLoS One. 2011;6(5):e19862
pubmed: 21625442
Cancer Genomics Proteomics. 2017 Nov-Dec;14(6):445-453
pubmed: 29109094
Science. 2019 Apr 26;364(6438):399-402
pubmed: 31023926
J Hepatol. 2016 Apr;64(1 Suppl):S17-S31
pubmed: 27084033
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Infection. 2020 Feb;48(1):7-17
pubmed: 31347138
J Biol Chem. 2006 Jun 16;281(24):16700-6
pubmed: 16595656
Cell Stem Cell. 2010 Jan 8;6(1):25-36
pubmed: 20085740
Am J Pathol. 2003 Aug;163(2):733-41
pubmed: 12875992