Organotypic liver culture models: Meeting current challenges in toxicity testing
Top Cited Papers
Open Access
- 15 May 2012
- journal article
- review article
- Published by Taylor & Francis in Critical Reviews in Toxicology
- Vol. 42 (6), 501-548
- https://doi.org/10.3109/10408444.2012.682115
Abstract
Prediction of chemical-induced hepatotoxicity in humans from in vitro data continues to be a significant challenge for the pharmaceutical and chemical industries. Generally, conventional in vitro hepatic model systems (i.e. 2-D static monocultures of primary or immortalized hepatocytes) are limited by their inability to maintain histotypic and phenotypic characteristics over time in culture, including stable expression of clearance and bioactivation pathways, as well as complex adaptive responses to chemical exposure. These systems are less than ideal for longer-term toxicity evaluations and elucidation of key cellular and molecular events involved in primary and secondary adaptation to chemical exposure, or for identification of important mediators of inflammation, proliferation and apoptosis. Progress in implementing a more effective strategy for in vitro-in vivo extrapolation and human risk assessment depends on significant advances in tissue culture technology and increasing their level of biological complexity. This article describes the current and ongoing need for more relevant, organotypic in vitro surrogate systems of human liver and recent efforts to recreate the multicellular architecture and hemodynamic properties of the liver using novel culture platforms. As these systems become more widely used for chemical and drug toxicity testing, there will be a corresponding need to establish standardized testing conditions, endpoint analyses and acceptance criteria. In the future, a balanced approach between sample throughput and biological relevance should provide better in vitro tools that are complementary with animal testing and assist in conducting more predictive human risk assessment.Keywords
This publication has 391 references indexed in Scilit:
- Modular bioreactor for primary human hepatocyte culture: Medium flow stimulates expression and activity of detoxification genesBiotechnology Journal, 2011
- Human hepatic stem cell and maturational liver lineage biologyHepatology, 2011
- Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fatesHepatology, 2010
- Co-culture of primary rat hepatocytes with rat liver epithelial cells enhances interleukin-6-induced acute-phase protein responseCell and tissue research, 2010
- Generation of functional human hepatic endoderm from human induced pluripotent stem cellsHepatology, 2009
- Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver developmentHepatology, 2008
- Rat hepatocyte spheroids formed by rocked technique maintain differentiated hepatocyte gene expression and functionHepatology, 2008
- Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescenceHepatology, 2008
- Activation of stem cells in hepatic diseasesCell and tissue research, 2007
- GTP‐binding proteins of the Rho/Rac family: regulation, effectors and functions in vivoBioEssays, 2007