Molecular Mechanisms Underlying the Dedifferentiation Process of Isolated Hepatocytes and Their Cultures
Abstract
Primary hepatocytes and their cultures are a simple but versatile, well-controlled, and relatively easy to handle in vitro system that is well-accepted for investigating xenobiotic biotransformation, enzyme induction and inhibition, and (biotransformation-mediated) hepatotoxicity. In addition, hepatocyte cultures have proven to be valuable tools in the study of liver physiology, viral hepatitis, and liver regeneration and are proposed as an alternative to orthotopic liver transplantation. It has been observed, however, that a number of liver-specific functions are progressively lost with time when hepatocytes are isolated and cultivated. These phenotypic changes are primarily the result of fundamental changes in gene expression concomitant with a diminished transcription of the relevant liver-specific genes, and can be interpreted as a 'dedifferentiation' of the isolated hepatocytes. Ischemia-reperfusion stress induced during the isolation process, disruption of the normal tissue architecture, as well as an adaptation to the in vitro environment are underlying factors and will be extensively discussed. A detailed description of the regulation of the hepatocyte phenotype in vivo in the first section of this review will help to understand the effect of these factors on hepatocyte gene expression. Although different approaches, mainly mimicking the in vivo hepatocyte environment, have been succesfully used to prevent or slow down the dedifferentiation of primary hepatocytes in m…
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Primary human hepatocytes lose differentiation/dedifferentiate in vitro, which is a known problem of in vitro liver models.
“Loss of differentiation of primary human hepatocytes (PHHs) ex vivo is a known problem of in vitro liver models.”
From Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices (2023) · cites this paper as Elaut et al., 2006[10]
A dedifferentiation-associated downregulation of albumin, HNF4A and its downstream targets in the cytochrome P450 enzyme group in primary hepatocyte cultures is well described.
“A dedifferentiation-associated downregulation of albumin, the liver-enriched transcription factor HNF4A and its downstream targets in the cytochrome P450 enzyme group in primary hepatocyte cultures is well described (Elaut et al., 2006[10]).”
From Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices (2023) · cites this paper as Elaut et al., 2006[10]
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Illuminating the Black Box of Reprogramming
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Primary hepatocytes and their cultures for the testing of drug-induced liver injury
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Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing
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Primary hepatocytes and their cultures in liver apoptosis research
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- Authors
- Elaut, G., Henkens, T., Papeleu, P., Snykers, S., Vinken, M., Vanhaecke, T., & Rogiers, V.
- Affiliations
- Vrije Universiteit Brussel (BE)
- Venue
- Current Drug Metabolism
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2006-08-01
- Volume
- 7
- Issue
- 6
- Pages
- 629-660
- ISSN
- 1389-2002 (ISSN-L)
- OpenAlex
- W2150031244
- Cited by
- 292
- References
- 0
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 6 · 2023: 9 · 2022: 18 · 2021: 26 · 2020: 20 · 2019: 16 · 2018: 21 · 2017: 16 · 2016: 16 · 2015: 13 · 2014: 14 · 2013: 17 · 2012: 16
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Drug Metabolism (publishedVersion)
- PubMed (publishedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- hepatocyte dedifferentiation, primary hepatocytes, hepatocyte culture, hepatocyte phenotype, gene expression, hepatocyte isolation, hepatocyte-like cells, hepatic progenitor cells, xenobiotic metabolism, liver regeneration
- MeSH terms
- Animals, Cell Communication, Cell Differentiation, Cells, Cultured, Extracellular Matrix, Gene Expression Regulation, Humans, Nitric Oxide, Phenotype, Eicosanoids, Cytokines, Apoptosis, Reactive Oxygen Species, Hepatocytes, Reactive Nitrogen Species, Cell Proliferation
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