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

• DOI: 10.1038/srep25187
• Publication Date: 2016-05-04T09:10:49Z
• Authors: Catherine C. Bell; Delilah F. G. Hen...; Sabrina M. L. Moro; Ewa Ellis; Joanne Walsh; Anna Renblom; Lisa Fredriksson ...; Anita C. A. Dankers; Frank Jacobs; Jan Snoeys; Rowena L. Sison-Y...; Rosalind E. Jenkins; Åsa Nordling; Souren Mkrtchian; B. Kevin Park; Neil R. Kitteringham; Christopher E. P....; Volker M. Lauschke; Magnus Ingelman-S...
• Keywords: Spheroid; Liver disease; Chronic liver disease; Liver function

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