ArticleArchives of toxicology2017
Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile.
Article in Archives of toxicology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed.
- Hepatitis B virus protein X promotes survival and loss of hepatocyte identity in a differentiated human liver organoid system.Cell death and differentiation · 2026Article
- The TUBA1B-G3BP2 Axis Sustains p65 Transcriptional Activity to Promote Hepatocellular Carcinoma Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Ceramide-mediated mitochondrial dysfunction in nonobese nonalcoholic fatty liver disease: A regulatory role for serine palmitoyltransferase subunit 2.Journal of cell communication and signaling · 2026Article
- Gene therapy for liver diseases: methods, challenges and opportunities.Journal of nanobiotechnology · 2026Review
- New approach methodologies to model liver fibrosis in metabolic dysfunction-associated steatohepatitis.BMB reports · 2026Review
- Single-cell transcriptomics of acetaminophen-induced responses in human 2D and 3D liver microtissues.Archives of toxicology · 2026Article
- ICMT deficiency ameliorates weight loss and mortality, but not tumor formation in a mouse model of liver cancer.Cell communication and signaling : CCS · 2026Article
- Beyond animal models: using human pluripotent stem cell-derived stem and progenitor cells to predict cytotoxicity in normal tissues.Pathology oncology research : POR · 2026Article
- In Vitro Assessment of Drug-Induced Liver Injury Using Three-Dimensional Cultured HepaSH Cells Derived From Chimeric Mouse Model With Humanized Liver.Journal of applied toxicology : JAT · 2025Article
- Hepatitis B virus is a stealth virus that minimizes proteomic and secretomic changes in primary human hepatocytes.The Journal of general virology · 2025Article
- Advancing hepatotoxicity assessment: current advances and future directions.Toxicological research · 2025Review
- In vitro liver models for toxicological research.Drug metabolism and pharmacokinetics · 2025Review
- Limitations of acetaminophen as a reference hepatotoxin for the evaluation of in vitro liver models.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Article
- Analysis of culture and RNA isolation methods for precision-cut liver slices from cirrhotic rats.Scientific reports · 2024Article
- Organoids as preclinical models of human disease: progress and applications.Medical review (2021) · 2024Review
- Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes.Redox report : communications in free radical research · 2023Article
- Single-cell metabolic profiling reveals subgroups of primary human hepatocytes with heterogeneous responses to drug challenge.Genome biology · 2023Article
- Improvements in Maturity and Stability of 3D iPSC-Derived Hepatocyte-like Cell Cultures.Cells · 2023Article
- Opportunities and challenges for hepatitis B cure.eGastroenterology · 2023Review
15 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors.
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Abstract
The application of primary human hepatocytes following isolation from human tissue is well accepted to be compromised by the process of dedifferentiation. This phenomenon reduces many unique hepatocyte functions, limiting their use in drug disposition and toxicity assessment. The aetiology of dedifferentiation has not been well defined, and further understanding of the process would allow the development of novel strategies for sustaining the hepatocyte phenotype in culture or for improving protocols for maturation of hepatocytes generated from stem cells. We have therefore carried out the first proteomic comparison of primary human hepatocyte differentiation. Cells were cultured for 0, 24, 72 and 168 h as a monolayer in order to permit unrestricted hepatocyte dedifferentiation, so as to reveal the causative signalling pathways and factors in this process, by pathway analysis. A total of 3430 proteins were identified with a false detection rate of <1 %, of which 1117 were quantified at every time point. Increasing numbers of significantly differentially expressed proteins compared with the freshly isolated cells were observed at 24 h (40 proteins), 72 h (118 proteins) and 168 h (272 proteins) (p < 0.05). In particular, cytochromes P450 and mitochondrial proteins underwent major changes, confirmed by functional studies and investigated by pathway analysis. We report the key factors and pathways which underlie the loss of hepatic phenotype in vitro, particularly those driving the large-scale and selective remodelling of the mitochondrial and metabolic proteomes. In summary, these findings expand the current understanding of dedifferentiation should facilitate further development of simple and complex hepatic culture systems.
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