Cited by 329Drug-Induced Hepatotoxicity and ProtectionAnimal testing and alternativesLiver physiology and pathology

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Comparison of Hepatic 2D Sandwich Cultures and 3D Spheroids for Long-term Toxicity Applications: A Multicenter Study

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Bell, Catherine C, Dankers, Anita C A, Lauschke, Volker M, Sison-Young, Rowena, Jenkins, Roz, Rowe, Cliff, Goldring, Chris E, Park, Kevin, Regan, Sophie L, Walker, Tracy, Schofield, Chris, Baze, Audrey, Foster, Alison J, Williams, Dominic P, van de Ven, Amy W M, Jacobs, Frank, Houdt, Jos van, Lähteenmäki, Tuula, Snoeys, Jan, Juhila, Satu, Richert, Lysiane, Ingelman-Sundberg, Magnus·2018·Toxicological Sciences

DOI 10.1093/toxsci/kfx289PMC PMC5888952

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Abstract

Primary human hepatocytes (PHHs) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within hours. This dedifferentiation can be ameliorated when PHHs are cultured in sandwich configuration (2Dsw), particularly when cultures are regularly re-overlaid with extracellular matrix, or as 3D spheroids. In this study, the 6 participating laboratories evaluated the robustness of these 2 model systems made from cryopreserved PHH from the same donors considering both inter-donor and inter-laboratory variability and compared their suitability for use in repeated-dose toxicity studies using 5 different hepatotoxins with different toxicity mechanisms. We found that expression levels of proteins involved in drug absorption, distribution, metabolism, and excretion, as well as catalytic activities of 5 different CYPs, were significantly higher in 3D spheroid cultures, potentially affecting the exposure of the cells to drugs and their metabolites. Furthermore, global proteomic analyses revealed that PHH in 3D spheroid configuration were temporally stable whereas proteomes from the same donors in 2Dsw cultures showed substantial alterations in protein expression patterns over the 14 days in culture. Overall, spheroid cultures were more sensitive to the hepatotoxic compounds investigated, particularly upon long-term exposures, across testing sites with little inter-laboratory or inter-donor variability. The data presented here suggest that repeated-dosing regimens improve the predictivity of in vitro toxicity assays, and that PHH spheroids provide a sensitive and robust system for long-term mechanistic studies of drug-induced hepatotoxicity, whereas the 2Dsw system has a more dedifferentiated phenotype and lower sensitivity to detect hepatotoxicity.

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Authors: Bell, C. C., Dankers, A. C. A., Lauschke, V. M., Sison-Young, R., Jenkins, R., Rowe, C., Goldring, C. E., Park, K., Regan, S. L., Walker, T., Schofield, C., Baze, A., Foster, A. J., Williams, D. P., van de Ven, A. W. M., Jacobs, F., Houdt, J. V., Lähteenmäki, T., Snoeys, J., Juhila, S., Richert, L., & Ingelman-Sundberg, M.
Affiliations: Karolinska Institutet (SE)
Janssen (Belgium) (BE)
University of Liverpool (GB)
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
AstraZeneca (United Kingdom) (GB)
GlaxoSmithKline (United Kingdom) (GB)
GlaxoSmithKline Research & Development Limited (United Kingdom) (GB)
KaLy Cell, Plobsheim, France
Orion Corporation (Finland) (FI)
Université Bourgogne Franche-Comté (FR)
Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden
ORCID: Bell, Catherine C
Dankers, Anita C A
Lauschke, Volker M
Walker, Tracy
Baze, Audrey
Foster, Alison J
Williams, Dominic P
Jacobs, Frank
Lähteenmäki, Tuula
Snoeys, Jan
Richert, Lysiane
Venue: Toxicological Sciences
Publisher: Oxford University Press (OUP)
Published: 2018-01-10
Volume: 162
Issue: 2
Pages: 655-666
ISSN: 1096-0929 (ISSN-L)
1096-6080
DOI: 10.1093/toxsci/kfx289
PMC: PMC5888952
OpenAlex: W2782718389
Cited by: 327
References: 47
Citations by year: 2026: 40 · 2025: 38 · 2024: 28 · 2023: 31 · 2022: 39 · 2021: 60 · 2020: 47 · 2019: 28 · 2018: 16
FWCI: 41.55
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
Locations: Toxicological Sciences (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Funders: AstraZeneca
Vetenskapsrådet (2015-02760, 2016-06222, 01154, 2016-01154, 2016-01153)
Medical Research Council (MR/L006758/1)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords: primary human hepatocytes, multicellular spheroids, drug-induced liver injury, hepatotoxicity, repeated-dose toxicity, hepatocyte dedifferentiation, cryopreserved hepatocytes, inter-laboratory variability, donor variability, cytochrome P450 expression
MeSH terms: Cell Survival, Cells, Cultured, Cytochrome P-450 Enzyme System, Dose-Response Relationship, Drug, Pharmaceutical Preparations, Humans, Male, Middle Aged, Models, Biological, Predictive Value of Tests, Time Factors, Cryopreservation, Toxicity Tests, Spheroids, Cellular, Coculture Techniques, Hepatocytes, Chemical and Drug Induced Liver Injury, Primary Cell Culture

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Comparison of Hepatic 2D Sandwich Cultures and 3D Spheroids for Long-term Toxicity Applications: A Multicenter Study

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