Modeling hepatitis C virus infection using human induced pluripotent stem cells

Schwartz, Robert E.; Trehan, Kartik; Andrus, Linda; Sheahan, Timothy P.; Ploß, Alexander; Duncan, Stephen A.; Rice, Charles M.; Bhatia, Sangeeta N.

doi:10.1073/pnas.1121400109

Cited by 196 publications

(176 citation statements)

References 25 publications

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“…7). Among these, the hepatocytespecific genes AFP, ALB, and GC, a member of the albumin gene family, were upregulated, suggesting that Huh7.5.1-8 cells have more differentiated hepatocytelike phenotypes that are favorable for HCV infection (15,29,(34)(35)(36). Girard et al previously showed that NTS is highly upregulated in HCV NS5A-expressing Huh7 cells (37) and may be associated with efficient HCV replication.…”

Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of an Huh.7.5.1-Derived Cell Clone Highly Permissive to Hepatitis C Virus

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of an Huh.7.5.1-Derived Cell Clone Highly Permissive to Hepatitis C Virus

et al. 2015

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“…Interestingly, the first iPSC model of human liver infectious disease has also been reported recently. Schwartz and the colleagues reported that human iPSChepatocytes could support the entire life cycle of hepatitis C virus (HCV) including inflammatory responses to the viral infection (Schwartz et al, 2012). This study did not only offer a novel infectious disease model to study HCV pathogenesis, but also enabled future research regarding how host genetics could impact viral infection using personalized iPSC models.…”

Section: Human Ipsc Derived Hepatocytes For Disease Modelingmentioning

confidence: 99%

Human induced pluripotent stem cells derived hepatocytes: rising promise for disease modeling, drug development and cell therapy

Liu

Belmonte

2012

Protein Cell

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Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells (iPSC) represent new promises for liver disease study and drug discovery. Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many functional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and facilitate drug development process. In this review, we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.

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“…The experimental conditions used to generate MPCCs, maintain iPSCs, and differentiate iHeps have all been previously described (12,15,16,19). For HBV infection of MPCCs and iHeps, cultures were pretreated for 24 h with dimethyl sulfoxide [0.01% (vol/vol)], JAKi (1 μM; EMD Millipore), TBK1 inhibitor (1 μM; EMD Millipore), IFN-β (1,000 U/mL; R&D Systems), or entecavir (120 nM; Cayman Chemicals), as indicated, followed by infection with HBV + patient plasma.…”

Section: Methodsmentioning

confidence: 99%

“…As a complementary approach that enables more facile genetic manipulation on an untransformed and isogenic hepatocyte background, we also sought to establish robust HBV infection in induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHeps) (15,16). These cells have demonstrated their utility for modeling inherited metabolic disorders (17), incorporating genetic manipulations (18), and supporting infection with HCV (19)(20)(21). During iHep generation, the progression of differentiation is characterized by the sequential emergence of various hepatocyte-specific host factors known to play a role in the HBV life cycle, such as the transcription factor HNF4α and the nuclear receptor RXR (22).…”

Section: Significancementioning

confidence: 99%

Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems

Shlomai

Schwartz

Ramanan³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis B virus (HBV) chronically infects 400 million people worldwide and is a leading driver of end-stage liver disease and liver cancer. Research into the biology and treatment of HBV requires an in vitro cell-culture system that supports the infection of human hepatocytes, and accurately recapitulates virus-host interactions. Here, we report that micropatterned cocultures of primary human hepatocytes with stromal cells (MPCCs) reliably support productive HBV infection, and infection can be enhanced by blocking elements of the hepatocyte innate immune response associated with the induction of IFN-stimulated genes. MPCCs maintain prolonged, productive infection and represent a facile platform for studying virus-host interactions and for developing antiviral interventions. Hepatocytes obtained from different human donors vary dramatically in their permissiveness to HBV infection, suggesting that factors-such as divergence in genetic susceptibility to infection-may influence infection in vitro. To establish a complementary, renewable system on an isogenic background in which candidate genetics can be interrogated, we show that inducible pluripotent stem cells differentiated into hepatocyte-like cells (iHeps) support HBV infection that can also be enhanced by blocking interferon-stimulated gene induction. Notably, the emergence of the capacity to support HBV transcriptional activity and initial permissiveness for infection are marked by distinct stages of iHep differentiation, suggesting that infection of iHeps can be used both to study HBV, and conversely to assess the degree of iHep differentiation. Our work demonstrates the utility of these infectious systems for studying HBV biology and the virus' interactions with host hepatocyte genetics and physiology.HBV persistence | innate immunity | viral hepatitis H epatitis B virus (HBV) is a small 3.2-kb DNA virus that selectively infects hepatocytes in the human liver (1). The global disease burden is large, with ∼400 million people chronically infected worldwide, of whom about one-third will develop severe HBV-related complications, such as cirrhosis and liver cancer. Lifelong treatment is often required because of the stable nature of viral episomal DNA, known as covalently closed circular DNA (cccDNA), which maintains basal levels in infected cell nuclei even upon nucleos(t)ide inhibitor treatment. To date, HBV research has been hampered by a distinct lack of robust infectious model systems that both support productive HBV infection and accurately mimic virus-host interactions. Recently, the bile acid pump sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a receptor for both HBV and hepatitis D virus (2), and overexpression of NTCP in hepatoma cell lines renders them susceptible to HBV infection. However, hepatoma cells are known to be defective in many cellular pathways implicated in the innate immune response (3, 4), metabolism (5), and cell proliferation (6), which may contribute to published contradictory evidence regarding the e...

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Modeling hepatitis C virus infection using human induced pluripotent stem cells

Cited by 196 publications

References 25 publications

Isolation and Characterization of an Huh.7.5.1-Derived Cell Clone Highly Permissive to Hepatitis C Virus

Isolation and Characterization of an Huh.7.5.1-Derived Cell Clone Highly Permissive to Hepatitis C Virus

Human induced pluripotent stem cells derived hepatocytes: rising promise for disease modeling, drug development and cell therapy

Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems

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