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Long-term culture of human liver tissue with advanced hepatic functions
Soon Seng Ng, … , Nam Joon Cho, Jeffrey S. Glenn
Soon Seng Ng, … , Nam Joon Cho, Jeffrey S. Glenn
Published June 2, 2017
Citation Information: JCI Insight. 2017;2(11):e90853. https://doi.org/10.1172/jci.insight.90853.
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Resource and Technical Advance Gastroenterology Infectious disease

Long-term culture of human liver tissue with advanced hepatic functions

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Abstract

A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver’s natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450–mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus. The tissues permit the assessment of antiviral agents and maintain their advanced functions for over 5 months in culture. This extended functionality enabled the prediction of a fatal human-specific hepatotoxicity caused by fialuridine (FIAU), which had escaped detection by preclinical models and short-term clinical studies. The results obtained with the engineered human liver tissue in this study provide proof-of-concept determination of human-specific drug metabolism, demonstrate the ability to support infection with human hepatitis virus derived from an infected patient and subsequent antiviral drug testing against said infection, and facilitate detection of human-specific drug hepatotoxicity associated with late-onset liver failure. Looking forward, the scalability and biocompatibility of the scaffold are also ideal for future cell replacement therapeutic strategies.

Authors

Soon Seng Ng, Anming Xiong, Khanh Nguyen, Marilyn Masek, Da Yoon No, Menashe Elazar, Eyal Shteyer, Mark A. Winters, Amy Voedisch, Kate Shaw, Sheikh Tamir Rashid, Curtis W. Frank, Nam Joon Cho, Jeffrey S. Glenn

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Figure 1

Fabrication of functional 3-dimensional hexagonally arrayed lobular human liver tissues.

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Fabrication of functional 3-dimensional hexagonally arrayed lobular huma...
(A) Schematic illustration of inverted colloidal crystal (ICC) scaffold fabrication. (B) Freestanding colloidal crystal lattice and (C) the resultant ICC with interconnected windows indicated by arrowheads and backbone of ICC indicated by asterisks. Morphology of fetal total liver cells in Col-I ICC (D) upon seeding and (E) 2 weeks after seeding. (F) Variable pressure scanning electron microscopy image demonstrating clusters of liver tissues with high interconnectivity across different ICC tiers. (G and H)Immunofluorescence imaging of engineered liver tissues 2 weeks after seeding for albumin (red) and DAPI (blue) costaining with (G) CK19 (green) or (H) vimentin (green). (I) Accumulation of Cholyl-L-lysyl-fluorescein (CLF) in liver tissues after 40 minutes of CLF incubation, followed by 40 minutes of washing. (J–L) Immunohistological images demonstrating heterogeneous populations within the engineered tissues stained for albumin (J), CK19 (K), and CD68 (L). Scale bars: 100 μm.

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