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Cited by 739Drug-Induced Hepatotoxicity and ProtectionLiver physiology and pathology3D Printing in Biomedical Research

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 F. G., Moro, Sabrina M. L., Ellis, Ewa, Walsh, Joanne, Renblom, Anna, Fredriksson Puigvert, Lisa, Dankers, Anita C. A. +11 more·2016·Scientific Reports
DOI 10.1038/srep25187PMC PMC4855186
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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.

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  • Primary cells maintain essential tissue-level interactions, structural organization, and functional stability, critical for modeling drug penetration, systemic toxicity, and tissue-specific response.

    “Furthermore, primary cells maintain essential tissue-level interactions, structural organization, and functional stability, which are critical for modeling drug penetration, systemic toxicity, and tissue-specific response (Bell et al. 2016).”

    From Primary cell cultures versus immortalized cell lines: critical comparative insights into biological fidelity and translational applications (2026) · cites this paper as Bell et al. 2016

    The Discussion (page unavailable) says that 3D primary human hepatocyte spheroids recapitulate aspects of liver structure and maintain liver-specific functions; the Results show their use in studying drug-induced liver injury. The claim extends those findings to primary cells generally. The passages do not establish that the model captures drug penetration or systemic toxicity. (LLM, conf=0.86)

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  • Multiple comparative studies indicate that spheroid cultures sustain elevated liver-specific functions such as albumin secretion, urea production, and drug-metabolizing enzyme activity, while demonstrating enhanced sensitivity to hepatotoxic compounds and a longer lifespan.

    “Multiple comparative studies indicate that spheroid cultures sustain elevated liver-specific functions, such as albumin secretion, urea production, and drug-metabolizing enzyme activity, while simultaneously demonstrating enhanced sensitivity to hepatotoxic compounds and a longer lifespan [26,27].”

    From The Hepatocyte Expansion Paradox: A Review of In Vitro Challenges and Advances (2026) · cites this paper as [26]

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  • Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models.

    “Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models.”

    From Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury (2017) · cites this paper as Bell et al. 2016

  • Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants.

    “Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants.”

    From Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury (2017) · cites this paper as Bell et al. 2016

  • Prolonged drug exposure of up to 28 days resulted in increased sensitivity for detection of DILI compounds amiodarone, bosentan, diclofenac, fialuridine, and tolcapone.

    “These data are in agreement with the findings of Bell et al. (2016) who noted prolonged drug exposure of up to 28 days resulted in increased sensitivity for detection of DILI compounds amiodarone, bosentan, diclofenac, fialuridine, and tolcapone (Bell et al. 2016).”

    From Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury (2017) · cites this paper as Bell et al. 2016

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Authors
Bell, C. C., Hendriks, D. F. G., Moro, S. M. L., Ellis, E., Walsh, J., Renblom, A., Fredriksson Puigvert, L., Dankers, A. C. A., Jacobs, F., Snoeys, J., Sison-Young, R. L., Jenkins, R. E., Nordling, Å., Mkrtchian, S., Park, B. K., Kitteringham, N. R., Goldring, C. E. P., Lauschke, V. M., & Ingelman-Sundberg, M.
Affiliations
  • Karolinska Institutet (SE)
  • Karolinska University Hospital (SE)
  • University of Liverpool (GB)
  • Janssen (Belgium) (BE)
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-05-04
Volume
6
Issue
1
Pages
25187-25187
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep25187
PMC
PMC4855186
OpenAlex
W2345415005
Cited by
739
References
47
Citations by year
2026: 67 · 2025: 75 · 2024: 60 · 2023: 69 · 2022: 73 · 2021: 76 · 2020: 87 · 2019: 74 · 2018: 90 · 2017: 51 · 2016: 15
FWCI
95.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • European Commission (115336)
  • Vetenskapsrådet
  • Technische Universität München
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
Keywords
primary human hepatocytes, hepatocyte spheroids, drug-induced liver injury, 3D cell culture, serum-free culture, hepatotoxicity, FIAU, chronic toxicity, cholestasis, steatosis, viral hepatitis, liver disease modeling, proteomics, interindividual variability
MeSH terms
Proof of Concept Study, Arabinofuranosyluracil, Cells, Cultured, Humans, Models, Biological, Spheroids, Cellular, Proteome, Hepatocytes, Chemical and Drug Induced Liver Injury

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