Human-induced Pluripotent Stem Cell-derived Hepatocyte Platform in Modeling of SARS-CoV-2 Infection

Overview

Journal JGH Open

Specialty Gastroenterology

Date 2024 Jul 15

PMID 39006099

Authors

Ruiqi Zhang

Rui Wei

Yangyang Yuan

Na Li

Yang Hu

Kwok-Hung Chan

Ivan Fan-Ngai Hung

Hung-Fat Tse

Affiliations

Soon will be listed here.

Abstract

Background And Aim: Currently, SARS-CoV-2 is still spreading rapidly and globally. A large proportion of patients with COVID-19 developed liver injuries. The human-induced pluripotent stem cell (iPSC)-derived hepatocytes recapitulate primary human hepatocytes and have been widely used in studies of liver diseases.

Methods: To explore the susceptibility of hepatocytes to SARS-CoV-2, we differentiated iPSCs to functional hepatocytes and tried infecting them with different MOI (1, 0.1, 0.01) of SARS-CoV-2.

Results: The iPSC-derived hepatocytes are highly susceptible to virus infection, even at 0.01 MOI. Other than the ancestral strain, iHeps also support the replication of SARS-CoV-2 variants including alpha, beta, theta, and delta. More interestingly, the ACE2 expression significantly upregulated after infection, suggesting a vicious cycle between virus infection and liver injury.

Conclusions: The iPSC-derived hepatocytes can support the replication of SARS-CoV-2, and this platform could be used to investigate the SARS-CoV-2 hepatotropism and hepatic pathogenic mechanisms.

References

Grzywa-Celinska A, Emeryk-Maksymiuk J, Szewczyk K, Krusinski A, Celinski R, Milanowski J . Acute liver injury in the course of COVID-19. Ann Agric Environ Med. 2021; 28(4):729-732. DOI: 10.26444/aaem/142232. View

Gao X, Zhang S, Gou J, Wen Y, Fan L, Zhou J . Spike-mediated ACE2 down-regulation was involved in the pathogenesis of SARS-CoV-2 infection. J Infect. 2022; 85(4):418-427. PMC: 9250808. DOI: 10.1016/j.jinf.2022.06.030. View

Barreto E, Cruz A, Veras F, Martins R, Bernardelli R, Paiva I . COVID-19-related hyperglycemia is associated with infection of hepatocytes and stimulation of gluconeogenesis. Proc Natl Acad Sci U S A. 2023; 120(21):e2217119120. PMC: 10214153. DOI: 10.1073/pnas.2217119120. View

Perez-Bermejo J, Kang S, Rockwood S, Simoneau C, Joy D, Silva A . SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19. Sci Transl Med. 2021; 13(590). PMC: 8128284. DOI: 10.1126/scitranslmed.abf7872. View

Cayo M, Cai J, DeLaForest A, Noto F, Nagaoka M, Clark B . JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology. 2012; 56(6):2163-71. PMC: 3900031. DOI: 10.1002/hep.25871. View

Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K . Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020; 323(20):2052-2059. PMC: 7177629. DOI: 10.1001/jama.2020.6775. View

Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y . Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020; 395(10236):1569-1578. PMC: 7190303. DOI: 10.1016/S0140-6736(20)31022-9. View

Marra F, Tacke F . Roles for chemokines in liver disease. Gastroenterology. 2014; 147(3):577-594.e1. DOI: 10.1053/j.gastro.2014.06.043. View

Brenner C, Galluzzi L, Kepp O, Kroemer G . Decoding cell death signals in liver inflammation. J Hepatol. 2013; 59(3):583-94. DOI: 10.1016/j.jhep.2013.03.033. View

10.

Wei R, Yang J, Cheng C, Ho W, Li N, Hu Y . CRISPR-targeted genome editing of human induced pluripotent stem cell-derived hepatocytes for the treatment of Wilson's disease. JHEP Rep. 2021; 4(1):100389. PMC: 8633686. DOI: 10.1016/j.jhepr.2021.100389. View

11.

Rashid S, Corbineau S, Hannan N, Marciniak S, Miranda E, Alexander G . Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest. 2010; 120(9):3127-36. PMC: 2929734. DOI: 10.1172/JCI43122. View

12.

Yip T, Lui G, Wong V, Chow V, Ho T, Li T . Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19. Gut. 2020; 70(4):733-742. DOI: 10.1136/gutjnl-2020-321726. View

13.

Fan Z, Chen L, Li J, Cheng X, Yang J, Tian C . Clinical Features of COVID-19-Related Liver Functional Abnormality. Clin Gastroenterol Hepatol. 2020; 18(7):1561-1566. PMC: 7194865. DOI: 10.1016/j.cgh.2020.04.002. View

14.

Yang J, Wang Y, Zhou T, Wong L, Tian X, Hong X . Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells. Stem Cell Reports. 2017; 8(3):605-618. PMC: 5355732. DOI: 10.1016/j.stemcr.2017.01.027. View

15.

Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A . Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020; 382(24):2327-2336. PMC: 7169476. DOI: 10.1056/NEJMoa2007016. View

16.

Markov P, Katzourakis A, Stilianakis N . Antigenic evolution will lead to new SARS-CoV-2 variants with unpredictable severity. Nat Rev Microbiol. 2022; 20(5):251-252. PMC: 8919145. DOI: 10.1038/s41579-022-00722-z. View

17.

Melquist S, Estepp K, Aleksandrovich Y, Lee A, Beiseker A, Hamedani F . COVID-19 presenting as fulminant hepatic failure: A case report. Medicine (Baltimore). 2020; 99(43):e22818. PMC: 7581048. DOI: 10.1097/MD.0000000000022818. View

18.

Sodeifian F, Seyedalhosseini Z, Kian N, Eftekhari M, Najari S, Mirsaeidi M . Drug-Induced Liver Injury in COVID-19 Patients: A Systematic Review. Front Med (Lausanne). 2021; 8:731436. PMC: 8488138. DOI: 10.3389/fmed.2021.731436. View

19.

Goldman J, Lye D, Hui D, Marks K, Bruno R, Montejano R . Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020; 383(19):1827-1837. PMC: 7377062. DOI: 10.1056/NEJMoa2015301. View

20.

Goyal P, Choi J, Pinheiro L, Schenck E, Chen R, Jabri A . Clinical Characteristics of Covid-19 in New York City. N Engl J Med. 2020; 382(24):2372-2374. PMC: 7182018. DOI: 10.1056/NEJMc2010419. View