Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus

Roelandt, Philip; Obeid, Susan; Paeshuyse, Jan; Vanhove, Jolien; Lommel, Alfons Van; Nahmias, Yaakov; Nevens, Frederik; Neyts, Johan; Verfaillie, Catherine M.

doi:10.1016/j.jhep.2012.03.030

Cited by 90 publications

(71 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, these hepatic-like cells also permitted direct in fection by patient sera. Similar findings were also recently reported with human embryonic stem cells (hESC)-derived hepatocytes demonstrating that these cells could be infected with JFH1 viruses and supported the complete HCV replication cycle (Roelandt, Obeid et al 2012). …”

Section: Hcv Replication Models In Primary Cells and Patient Isolatessupporting

confidence: 87%

Cell Culture Systems for Hepatitis C Virus

Steinmann

Pietschmann

2013

Current Topics in Microbiology and Immunology

View full text Add to dashboard Cite

Due to the obligatory intracellular life style of viruses, cell culture systems for efficient viral propagation are crucial to obtain a detailed understanding of the virus host cell interaction. For hepatitis C virus (HCV) the development of permissive and authentic culture models has been and continues to be a challenging task. The first ef forts to culture HCV had limited success and range back to before the virus was molecularly cloned in 1989. Since then several major breakthroughs have gradually overcome limitations in culturing the virus and sequentially permitted analysis of viral RNA replication, cell entry and ultimately the complete replication cycle in cultured cells in 2005. Until today, basic and applied HCV research greatly benefit from these tremendous efforts which spurred multiple com plementary cell based model systems for distinct steps of the HCV replication cycle. When used in combination they now permit deep insights into the fascinating biology of HCV and its interplay with the host cell. In fact drug development has been much facilitated and our understanding of the molecular determinants of HCV replication has grown in parallel to these advances. Building on this ground work and further refining our cellular models to better mimic the ar chitecture, polarization and differentiation of natural hepatocytes should reveal novel unique aspects of HCV replication. Ultimately, models to culture primary HCV isolates across all genotypes may teach us important new lessons about viral functional adaptations that have evolved in exchange with its human host and that may ex plain the variable natural course of hepatitis C.

show abstract

Section: Hcv Replication Models In Primary Cells and Patient Isolatessupporting

confidence: 87%

Cell Culture Systems for Hepatitis C Virus

Steinmann

Pietschmann

2013

Current Topics in Microbiology and Immunology

View full text Add to dashboard Cite

show abstract

“…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: 98%

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

et al. 2015

View full text Add to dashboard Cite

“…Several reports have shown that hepatic differentiation is involved in the susceptibility of ES/iPS cells to HCVcc infection (28,30,41). In addition, in hepatic cancer cell lines, including Huh7, HepG2, and Hep3B, cells derived from not poorly but well-differentiated HCC permit complete propagation of HCVcc (15)(16)(17), suggesting that hepatic differentiation is closely related to the susceptibility of cells to HCVcc propagation.…”

Section: Discussionmentioning

confidence: 99%

“…AFP is known as a marker for not only well-differentiated HCC (31) but also the early stage of differentiation to hepatocytes in embryonic stem (ES)/iPS cells (29,40,41). Generally, well-differentiated cancer cells show better maintenance of their cell-specific functions than poorly differentiated cancer cells.…”

Section: Jhh-4 and Fu97 Cells Express High Levels Of The Liver-specifmentioning

confidence: 99%

Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

Mai

Fukuhara

Ono

et al. 2014

J Virol

View full text Add to dashboard Cite

Hepatitis C virus (HCV) is a major etiologic agent of chronic liver diseases. Although the HCV life cycle has been clarified by studying laboratory strains of HCV derived from the genotype 2a JFH-1 strain (cell culture-adapted HCV [HCVcc]), the mechanisms of particle formation have not been elucidated. Recently, we showed that exogenous expression of a liver-specific microRNA, miR-122, in nonhepatic cell lines facilitates efficient replication but not particle production of HCVcc, suggesting that liver-specific host factors are required for infectious particle formation. In this study, we screened human cancer cell lines for expression of the liver-specific ␣-fetoprotein by using a cDNA array database and identified liver-derived JHH-4 cells and stomach-derived FU97 cells, which express liver-specific host factors comparable to Huh7 cells. These cell lines permit not only replication of HCV RNA but also particle formation upon infection with HCVcc, suggesting that hepatic differentiation participates in the expression of liver-specific host factors required for HCV propagation. HCV inhibitors targeting host and viral factors exhibited different antiviral efficacies between Huh7 and FU97 cells. Furthermore, FU97 cells exhibited higher susceptibility for propagation of HCVcc derived from the JFH-2 strain than Huh7 cells. These results suggest that hepatic differentiation participates in the expression of liver-specific host factors required for complete propagation of HCV. IMPORTANCEPrevious studies have shown that liver-specific host factors are required for efficient replication of HCV RNA and formation of infectious particles. In this study, we screened human cancer cell lines for expression of the liver-specific ␣-fetoprotein by using a cDNA array database and identified novel permissive cell lines for complete propagation of HCVcc without any artificial manipulation. In particular, gastric cancer-derived FU97 cells exhibited a much higher susceptibility to HCVcc/JFH-2 infection than observed in Huh7 cells, suggesting that FU97 cells would be useful for further investigation of the HCV life cycle, as well as the development of therapeutic agents for chronic hepatitis C. More than 170 million individuals worldwide are infected with hepatitis C virus (HCV), and the cirrhosis and hepatocellular carcinoma induced by HCV infection are life-threatening diseases (1). Current standard therapy combining pegylated-interferon (peg-IFN) and ribavirin (RBV) has achieved a sustained virological response (SVR) in 50% of individuals infected with HCV genotype 1 (2). Recently, directly acting antiviral (DAA) agents have been applied in a clinical setting (3). An SVR rate of over 80% has been realized by combination therapy with peg-IFN, RBV, and NS3/4A inhibitors in genotype 1 patients (4, 5). In addition, several DAAs, including inhibitors for NS3/4A protease, NS5A, and NS5B polymerase, are currently in clinical trials. Several reports have shown that in vitro replication of HCV RNA is significantly inhibited by treat...

show abstract

Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus

Cited by 90 publications

References 25 publications

Cell Culture Systems for Hepatitis C Virus

Cell Culture Systems for Hepatitis C Virus

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

Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

Contact Info

Product

Resources

About