Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Godoy, Patricio; Hewitt, Nicola J.; Albrecht, Ute; Andersen, Melvin E.; Ansari, Nariman; Bhattacharya, Sudin; Bode, Johannes Georg; Bolleyn, Jennifer; Borner, Christoph; Böttger, Jan; Braeuning, Albert; Budinsky, Robert A.; Burkhardt, Britta; Cameron, Neil R.; Camussi, Giovanni; Cho, Chong-Su; Choi, Yun-Jaie; Craig Rowlands, J.; Dahmen, Uta; Damm, Georg; Dirsch, Olaf; Donato, María Teresa; Dong, Jian; Dooley, Steven; Drasdo, Dirk; Eakins, Rowena; Ferreira, Karine Sá; Fonsato, Valentina; Fraczek, Joanna; Gebhardt, Rolf; Gibson, Andrew; Glanemann, Matthias; Goldring, Chris E. P.; Gómez-Lechón, María José; Groothuis, Geny M. M.; Gustavsson, Lena; Guyot, Christelle; Hallifax, David; Hammad, Seddik; Hayward, Adam; Häussinger, Dieter; Hellerbrand, Claus; Hewitt, Philip; Hoehme, Stefan; Holzhütter, Hermann-Georg; Houston, J. Brian; Hrach, Jens; Ito, Kiyomi; Jaeschke, Hartmut; Keitel, Verena

doi:10.1007/s00204-013-1078-5

Cited by 1,280Drug-Induced Hepatotoxicity and ProtectionLiver physiology and pathologyAnimal testing and alternatives

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

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Godoy, Patricio, Hewitt, Nicola J., Albrecht, Ute, Andersen, Melvin E., Ansari, Nariman, Bhattacharya, Sudin, Bode, Johannes Georg, Bolleyn, Jennifer +85 more·2013·Archives of Toxicology

DOI 10.1007/s00204-013-1078-5PMC PMC3753504

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Abstract

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

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In the first few days of PHH cultivation, hepatic functions such as plasma protein production, drug metabolizing enzyme activities, glucose metabolism and urea synthesis are reduced.
“Already in the first few days of cultivation, a reduction of hepatic functions can be observed, e.g. production of plasma proteins, drug metabolizing enzyme activities, glucose metabolism and urea synthesis (Godoy et al., 2013[15]).”
From Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices (2023) · cites this paper as Godoy et al., 2013[15]
The 3D liver models section (page unavailable) says hepatocyte dedifferentiation in 2D culture reduces plasma-protein production and detoxification associated with phase I and II enzymes. But the Isolated human hepatocytes section says enzyme activities, glucose metabolism and ammonia detoxification can remain functional for at least 48–72 hours; it does not establish that glucose metabolism or urea synthesis decline in the first few days. The citing sentence therefore overstates which functions the review identifies as declining at that time. (LLM, conf=0.86)
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Primary human hepatocytes are an important tool for studying human liver disease and drug-induced liver injury, and other models such as rat hepatocytes, hepatic cell lines and stem cell-derived hepatocyte-like cells fail to offer metabolically competent and species-relevant alternatives.
“Primary human hepatocytes (PHHs) are an important tool for studying human liver disease and drug-induced liver injury (DILI), with other models, such as rat hepatocytes, hepatic cell lines and stem cell-derived hepatocyte-like cells failing to offer metabolically competent and species-relevant alternatives (Godoy et al. 2013).”
From Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile (2017) · cites this paper as Godoy et al. 2013
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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Zonation appears to be a large influencing factor on variation during culture, as pathway analysis of the most variable proteins revealed significant association with ketogenesis, cholesterol biosynthesis, fatty acid beta oxidation and glutamine synthesis, all related to the portocentral axis gradient of the lobule.
“In fact, zonation appears to be a large influencing factor on variation during culture as our pathway analysis of the most variable proteins revealed significant association with ketogenesis, cholesterol biosynthesis, fatty acid β oxidation and glutamine synthesis (table S4), all of these are related to the portocentral axis gradient of the lobule (Godoy et al. 2013).”
From Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile (2017) · cites this paper as Godoy et al. 2013
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Although cytotoxicity measures are fundamental in assessing a drug's potential for hepatotoxicity in vitro, gene expression and various phenotypic changes can occur at much lower concentrations.
“although cytotoxicity measures are fundamental in the assessment of a drug’s potential for hepatotoxicity in vitro33,34, gene expression and various phenotypic changes can occur at much lower concentrations35,36.”
From Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology (2022) · cites this paper as [34]
The apical membrane is equipped with transport proteins such as MRP2 that eliminate bile acids and xenobiotics from the cell.
“The apical membrane is equipped with transport proteins that eliminate bile acids and xenobiotics from the cell, like multidrug resistance-associated protein 2 (MRP2) (Godoy et al., 2013[15]; Ito et al., 2005[20]).”
From Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices (2023) · cites this paper as Godoy et al., 2013[15]

The hepatocyte basal membrane faces the sinusoid and expresses transmembrane transporters that manage exchange of substances with the sinusoidal blood stream.
“The hepatocyte's basal membrane faces the sinusoid. It expresses several transmembrane transporters that manage the exchange of substances with the sinusoidal blood stream (Godoy et al., 2013[15]).”
From Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices (2023) · cites this paper as Godoy et al., 2013[15]
In vivo, the distribution of ECM components varies between different parts of the liver acinus.
“In vivo, the distribution of ECM components varies between the different parts of the liver acinus, the smallest organizational unit of the liver (Godoy et al., 2013[15]; Martinez-Hernandez and Amenta, 1993[26]).”
From Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices (2023) · cites this paper as Godoy et al., 2013[15]
Primary human hepatocytes undergo rapid dedifferentiation following isolation, losing many unique hepatocyte characteristics and reducing the physiological relevance of the model.
“The application of primary human hepatocytes following isolation from human tissue is well accepted to be compromised by the process of dedifferentiation.”
From Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile (2017) · cites this paper as Godoy et al. 2013
Strategies for optimizing HepG2 can be divided into genetic modification to express key biotransformation enzymes, epigenetic and cultural maturation, external metabolic activation using subcellular liver fractions (S9 or microsomes), and transitioning from monolayer culture to 3D or hybrid formats.
“In practice, strategies for optimizing HepG2 can be divided into several approaches. The first approach is based on genetic modification of cells to express key biotransformation enzymes, in particular cytochrome P450 isoforms [109]. The second approach involves epigenetic and cultural maturation of cells, which allows for increased expression of nuclear receptors and, consequently, of xenobiotic”
From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [163]
The citation is attached to the first approach: genetically modifying HepG2 cells to express biotransformation enzymes, particularly cytochrome P450 isoforms. The Hydrogel 3D scaffolds section reports increased CYP1A1 expression in HepG2 spheroids, but does not describe genetic modification as the cause. Searches for transfected or engineered HepG2 cells found no passage in the available body text establishing that approach; our copy may be truncated. (LLM, conf=0.68)
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Authors: Godoy, P., Hewitt, N. J., Albrecht, U., Andersen, M. E., Ansari, N., Bhattacharya, S., Bode, J. G., Bolleyn, J., Borner, C., Böttger, J., Braeuning, A., Budinsky, R. A., Burkhardt, B., Cameron, N. R., Camussi, G., Cho, C.-S., Choi, Y.-J., Craig Rowlands, J., Dahmen, U., Damm, G., Dirsch, O., Donato, M. T., Dong, J., Dooley, S., Drasdo, D., Eakins, R., Ferreira, K. S., Fonsato, V., Fraczek, J., Gebhardt, R., Gibson, A., Glanemann, M., Goldring, C. E. P., Gómez-Lechón, M. J., Groothuis, G. M. M., Gustavsson, L., Guyot, C., Hallifax, D., Hammad, S., Hayward, A., Häussinger, D., Hellerbrand, C., Hewitt, P., Hoehme, S., Holzhütter, H.-G., Houston, J. B., Hrach, J., Ito, K., Jaeschke, H., Keitel, V., Kelm, J. M., Kevin Park, B., Kordes, C., Kullak-Ublick, G. A., LeCluyse, E. L., Lu, P., Luebke-Wheeler, J., Lutz, A., Maltman, D. J., Matz-Soja, M., McMullen, P., Merfort, I., Messner, S., Meyer, C., Mwinyi, J., Naisbitt, D. J., Nussler, A. K., Olinga, P., Pampaloni, F., Pi, J., Pluta, L., Przyborski, S. A., Ramachandran, A., Rogiers, V., Rowe, C., Schelcher, C., Schmich, K., Schwarz, M., Singh, B., Stelzer, E. H. K., Stieger, B., Stöber, R., Sugiyama, Y., Tetta, C., Thasler, W. E., Vanhaecke, T., Vinken, M., Weiss, T. S., Widera, A., Woods, C. G., Xu, J. J., Yarborough, K. M., & Hengstler, J. G.
Affiliations: University of Zurich (CH)
Leibniz Research Centre for Working Environment and Human Factors (DE)
The Hamner Institutes for Health Sciences (US)
Goethe University Frankfurt (DE)
Vrije Universiteit Brussel (BE)
University of Freiburg (DE)
Leipzig University (DE)
Dow Chemical (United States) (US)
Durham University (GB)
Seoul National University (KR)
Instituto de Investigación Sanitaria La Fe (ES)
Heidelberg University (DE)
University of Liverpool (GB)
University of Groningen (NL)
Lund University (SE)
University of Manchester (GB)
South Valley University (EG)
Heinrich Heine University Düsseldorf (DE)
University Hospital Regensburg (DE)
Merck KGaA, Darmstadt (Germany) (DE)
Charité – Universitätsmedizin Berlin (DE)
Musashino University (JP)
University Hospital Zurich (CH)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author: Hewitt, Nicola J.
ORCID: Hewitt, Nicola J.
Andersen, Melvin E.
Bhattacharya, Sudin
Bode, Johannes Georg
Borner, Christoph
Böttger, Jan
Braeuning, Albert
Budinsky, Robert A.
Cameron, Neil R.
Camussi, Giovanni
Cho, Chong-Su
Choi, Yun-Jaie
Dahmen, Uta
Damm, Georg
Dirsch, Olaf
Donato, María Teresa
Dong, Jian
Dooley, Steven
Drasdo, Dirk
Gibson, Andrew
Glanemann, Matthias
Groothuis, Geny M. M.
Hallifax, David
Hammad, Seddik
Hayward, Adam
Häussinger, Dieter
Hellerbrand, Claus
Hewitt, Philip
Hoehme, Stefan
Holzhütter, Hermann-Georg
Houston, J. Brian
Ito, Kiyomi
Jaeschke, Hartmut
Keitel, Verena
Kordes, Claus
Kullak-Ublick, Gerd A.
LeCluyse, Edward L.
Maltman, Daniel J.
McMullen, Patrick
Merfort, Irmgard
Meyer, Christoph
Mwinyi, Jessica
Naisbitt, Dean J.
Nussler, Andreas K.
Olinga, Peter
Pampaloni, Francesco
Pi, Jingbo
Pluta, Linda
Przyborski, Stefan A.
Ramachandran, Anup
Rogiers, Vera
Schwarz, Michael
Singh, Bijay
Stelzer, Ernst H. K.
Stieger, Bruno
Sugiyama, Yuichi
Vanhaecke, Tamara
Vinken, Mathieu
Weiss, Thomas S.
Woods, Courtney G.
Hengstler, Jan G.
Venue: Archives of Toxicology
Publisher: Springer Science and Business Media LLC
Published: 2013-08
Volume: 87
Issue: 8
Pages: 1315-1530
ISSN: 0340-5761 (ISSN-L)
1432-0738
DOI: 10.1007/s00204-013-1078-5
PMC: PMC3753504
OpenAlex: W2134520937
Cited by: 1,280
References: 1,862
Citations by year: 2026: 54 · 2025: 63 · 2024: 59 · 2023: 80 · 2022: 98 · 2021: 96 · 2020: 130 · 2019: 132 · 2018: 129 · 2017: 102 · 2016: 118 · 2015: 110 · 2014: 91 · 2013: 12
FWCI: 18.06
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: other-oa
creativecommons.org/licenses/by-nc/2.0 (unspecified)
Locations: Archives of Toxicology (publishedVersion, other-oa)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (publishedVersion)
University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
Durham Research Online (Durham University) (acceptedVersion, other-oa)
Durham Research Online (Durham University) (submittedVersion, cc-by)
HAL (submittedVersion)
Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Lund University Publications (Lund University) (submittedVersion, other-oa)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, cc-by-nc)
VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
Zurich Open Repository and Archive (University of Zurich)
University of Regensburg Publication Server (University of Regensburg)
Funders: Leibniz-Institut für Arbeitsforschung an der TU Dortmund
Deutsche Forschungsgemeinschaft (GRK1104, (EXC 294))
Agence Nationale de la Recherche
Bundesministerium für Bildung und Forschung
Belgian Federal Science Policy Office
Fonds Wetenschappelijk Onderzoek
National Research Foundation of Korea
Innoviris
Universität Regensburg
Vlaamse regering
National Institutes of Health (AA12916)
Biotechnology and Biological Sciences Research Council (1233823)
Leibniz-Gemeinschaft
Japan Society for the Promotion of Science (23590204)
National Institute on Alcohol Abuse and Alcoholism (R56AA012916, R01AA012916)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK070195)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords: hepatotoxicity, primary hepatocytes, non-parenchymal liver cells, hepatocyte co-culture, precision-cut liver slices, isolated perfused liver, stem cell-derived hepatocytes, induced pluripotent stem cell-derived hepatocytes, nuclear receptors, Ras/MEK/ERK pathway, HNF4α, drug metabolism, ADME, drug interactions
MeSH terms: Animals, Gene Expression Regulation, Humans, Liver, Inactivation, Metabolic, Organ Culture Techniques, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Toxicity Tests, Coculture Techniques, Hepatocytes, Toxicogenetics, Culture Techniques, High-Throughput Screening Assays

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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

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