Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

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Bell, Catherine C, Hendriks, Delilah FG, Moro, Sabrina ML, Ellis, Ewa, Walsh, Joanne, Renblom, Anna, Fredriksson Puigvert, Lisa, Dankers, Anita CA, Jacobs, Frank, Snoeys, Jan et al (show 9 more authors) , Sison-Young, Rowena L, Jenkins, Rosalind E, Nordling, Åsa, Mkrtchian, Souren, Park, B Kevin ORCID: 0000-0001-8384-824X, Kitteringham, Neil R, Goldring, Christopher EP, Lauschke, Volker M and Ingelman-Sundberg, Magnus (2016) Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Scientific Reports, 6 (1). 25187-.

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Abstract

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI.

Item Type:	Article
Uncontrolled Keywords:	Cells, Cultured, Spheroids, Cellular, Hepatocytes, Humans, Proteome, Arabinofuranosyluracil, Models, Biological, Chemical and Drug Induced Liver Injury, Proof of Concept Study
Depositing User:	Symplectic Admin
Date Deposited:	07 Apr 2017 14:38
Last Modified:	19 Jan 2023 07:06
DOI:	10.1038/srep25187
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3006890

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• Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. (deposited 07 Sep 2016 08:57)
  • Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. (deposited 07 Apr 2017 14:38) [Currently Displayed]