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- Title
Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment.
- Authors
Ip, Blanche C; Madnick, Samantha J; Zheng, Sophia; Tongeren, Tessa C A van; Hall, Susan J; Li, Hui; Martin, Suzanne; Spriggs, Sandrine; Carmichael, Paul; Chen, Wei; Ames, David; Breitweiser, Lori A; Pence, Heather E; Bowling, Andrew J; Johnson, Kamin J; Cubberley, Richard; Morgan, Jeffrey R; Boekelheide, Kim
- Abstract
Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This 2-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue). The target tissue chamber can be configured to accommodate a three-dimensional (3D) spheroid-shaped microtissue, or a 2-dimensional (2D) cell monolayer. Culture medium and compounds freely diffuse between the 2 chambers. Human-differentiated HepaRG liver cells are used to form the 3D human liver microtissues, which displayed robust protein expression of liver biomarkers (albumin, asialoglycoprotein receptor, Phase I cytochrome P450 [CYP3A4] enzyme, multidrug resistance-associated protein 2 transporter, and glycogen), and exhibited Phase I/II enzyme activities over the course of 17 days. Histological and ultrastructural analyses confirmed that the HepaRG microtissues presented a differentiated hepatocyte phenotype, including abundant mitochondria, endoplasmic reticulum, and bile canaliculi. Liver microtissue zonation characteristics could be easily modulated by maturation in different media supplements. Furthermore, our proof-of-concept study demonstrated the efficacy of this coculture model in evaluating testosterone-mediated androgen receptor responses in the presence of human liver metabolism. This liver-organ coculture system provides a practical, higher-throughput testing platform for metabolism-dependent bioactivity assessment of drugs/chemicals to better recapitulate the biological effects and potential toxicity of human exposures.
- Subjects
MICROPHYSIOLOGICAL systems; CHEMICAL safety; MULTIDRUG resistance-associated proteins; ATP-binding cassette transporters; LIVER cells; LIVER; ANDROGEN receptors; CELL culture
- Publication
Toxicological Sciences, 2024, Vol 199, Issue 2, p227
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kfae018