The HepaRG Cell Line: Biological Properties and Relevance as a Tool for Cell Biology, Drug Metabolism, and Virology Studies

Abstract

Liver progenitor cells may play an important role in carcinogenesis in vivo and represent therefore useful cellular materials for in vitro studies. The HepaRG cell line, which is a human bipotent progenitor cell line capable to differentiate toward two different cell phenotypes (i.e., biliary-like and hepatocyte-like cells), has been established from a liver tumor associated with chronic hepatitis C. This cell line represents a valuable alternative to ex vivo cultivated primary human hepatocytes (PHH), as HepaRG cells share some features and properties with adult hepatocytes. The cell line is particularly useful to evaluate drugs and perform drug metabolism studies, as many detoxifying enzymes are expressed and functional. It is also an interesting tool to study some aspect of progenitor biology (e.g., differentiation process), carcinogenesis, and the infection by some pathogens for which the cell line is permissive (e.g., HBV infection). Overall, this chapter gives a concise overview of the biological properties and potential applications of this cell line.

Characterization of the Inflammasome in Human Kupffer Cells in Response to Synthetic Agonists and Pathogens

“…2A). The lack of functional AIM2 and NLRP3 inflammasomes in hepatocytes was further confirmed in HepaRG cells devoid of contaminating immune cells (25). As observed in KC-depleted PCHH, neither IL-1b nor IL-18 production was detected in the HepaRG cells after AIM2 or NLRP3 inflammasome activation (Supplemental Fig.…”

“…0.0001. in liver macrophages (CD68 + /CD14 + ). TLR8 induction of IL-18 and IL-12 was reported in infiltrating liver macrophages and MAIT cells in normal and in HBV-and HCV-infected livers (25).…”

Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

“…First, during differentiation, HepaRG cells evolve from a homogeneous depolarized epithelial phenotype showing no specific organization into a structurally well-defined and polarized monolayer that closely resembles those formed by primary human hepatocytes in culture [10]. Secondly, these cells show long-term stability in terms of various mature hepatocyte functions, including iron storage, cytochrome P450 enzyme activities and albumin secretion [11]; Thirdly, polarized hepatocyte-like cells differentiated from HepaRG cells mimic mature primary human hepatocytes (PHHs) [12], as evidenced by the fact that they can support the in vitro infection and replication of human hepatitis B virus (HBV) [13], a feature that has not been observed in hepatocyte-like cells generated from other stem cell systems. Thus, the HepaRG cell line has become a promising in vitro model to determine not only the basic regulation of hepatic cell fate but also the maturation into hepatocytes.…”

Very-Low-Density Lipoprotein (VLDL)-Producing and Hepatitis C Virus-Replicating HepG2 Cells Secrete No More Lipoviroparticles than VLDL-Deficient Huh7.5 Cells

“…We observed transient replication in both HepG2-CD81 and HepG2-CD81-shIFN-␤-shIFNAR1 (a cell line impaired in IFN responses as previously reported [60]) cells, suggesting that ATCC-derived HepG2 cells, with a knocked down IFN response, do not support sustained HCV replication (Table 1). Furthermore, differentiated HepaRG cells, a hepatic bipotent progenitor cell line (61,62), and freshly isolated primary human hepatocytes (PHH) showed transient resistance to blasticidin, with no stable cell lines being generated under our experimental conditions (Table 1). Stably replicating HepG2 cells were obtained only with cured HepG2 cells, which had previously replicated subgenomic HCV replicons.…”