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. 2019 Dec 24;3(4):040902. doi: 10.1063/1.5119090

FIG. 1.

FIG. 1.

In vitro human liver models of HBV and NAFLD. (a) Infection of MPCCs with HBV.38 Left to right: Phase contrast image of a PHH island surrounded by 3T3-J2 fibroblasts. Schematic of HBV infection and lifecycle inside a hepatocyte. Viral antigens and cccDNA are detectable in MPCCs at higher levels when the cultures are incubated with a small molecule inhibitor of JAK. Reprinted with permission from Shlomai et al., Proc. Natl. Acad. Sci. 111(33), 12193 (2014). Copyright 2014 National Academy of Sciences. (b) HBV infection in the LiverChip.40 Left: Bioreactor cross section schematic showing the fluid flow direction and polycarbonate filter on which cells attach in spheroidal structures. Middle: HBV antigens (HBV “e” antigen or HBeAg in green; HBV “core” antigen or HBcAg in red; nuclei are in blue) were present in the self-assembled spheroids within the chip following infection with HBV. Scale bars: white (200 μm), gray (100 μm). Right: HBeAg and HBV DNA secretion in supernatants of HBV-infected cultures in the LiverChip ± treatment with HBV drug, tenofovir alafenamide (TAF, 1 μM, 10 day treatment). Reprinted with permission from Ortega-Prieto et al., Nat. Commun. 9(1), 682 (2018); Copyright 2018 Author(s), licensed under a Creative Commons Attribution (CC BY) license. (c) PHHs in MPCCs treated with a hyperglycemic culture medium for 18 days become steatotic (green: Nile red, stains neutral lipids).52 Scale bars are 400 μm. Reprinted with permission from Davidson et al., Sci. Rep. 6, 28178 (2016). Copyright 2016 Authors, licensed under a Creative Commons Attribution (CC BY) license. (d) Self-assembled PHH spheroids created using ultralow attachment plates can be made steatotic (green: Nile red stain for neutral lipids; blue: nuclei stained with Hoechst 33342) by incubating over time with varying concentrations of insulin and free fatty acids (FFA).54 with permission Kozyra et al., Sci. Rep. 8(1), 14297 (2018). Copyright 2018 Author(s), licensed under a Creative Commons Attribution (CC BY) license. (e) MPTCs containing PHHs, 3T3-J2 fibroblasts, and activated (fibrogenic) HSCs.34 Left to right: Fluorescence images showing albumin (ALB) positive PHHs, alpha smooth muscle actin (alpha-SMA) positive activated HSCs, and collagen (COL-1) deposition by the HSCs as in liver fibrosis. CYP3A4 enzyme activity in PHHs is downregulated with the addition of increasing numbers of HSCs in the MPTC model. Higher levels of inflammatory cytokine, interleukin-6 (IL-6), are secreted from MPTCs with increasing numbers of fibrogenic HSCs. Reprinted with permission from Davidson et al., Integr. Biol. 9(8), 662. Copyright 2017 Oxford University Press.