开发用于高通量化学品安全评估的人类肝脏微生理共培养系统。

IF 3.4 3区 医学 Q2 TOXICOLOGY
Blanche C Ip, Samantha J Madnick, Sophia Zheng, Tessa C A van Tongeren, Susan J Hall, Hui Li, Suzanne Martin, Sandrine Spriggs, Paul Carmichael, Wei Chen, David Ames, Lori A Breitweiser, Heather E Pence, Andrew J Bowling, Kamin J Johnson, Richard Cubberley, Jeffrey R Morgan, Kim Boekelheide
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引用次数: 0

摘要

与母体化合物相比,全身循环中的化学品会发生肝脏异生物代谢,产生代谢物并表现出不同的毒性。本文介绍了一种双室肝脏器官共培养模型,该模型采用高通量 96 孔格式,可在与人体生理相关的肝脏代谢过程中测定对靶组织的毒性。该双室系统是在每个孔内形成的水凝胶,包括一个中心孔(靶组织)和一个外环形槽(人体肝脏组织)。靶组织室可配置为容纳三维(3D)球形微组织或二维(2D)单层细胞。培养基和化合物可在两个腔室之间自由扩散。人体分化的 HepaRGTM 肝细胞用于形成三维人体肝脏微组织,在 17 天的过程中,肝脏生物标志物(白蛋白、asialoglycoprotein 受体、I 期细胞色素 P450 (CYP3A4) 酶、多药耐药性相关蛋白 2 转运体和糖原)的蛋白质表达活跃,并显示出 I/II 期酶的活性。组织学和超微结构分析证实,HepaRG 微组织呈现分化的肝细胞表型,包括丰富的线粒体、内质网和胆管。肝脏微组织的分区特征很容易通过在不同培养基补充物中的成熟来调节。此外,我们的概念验证研究证明了这种共培养模型在评估睾酮介导的雄激素受体在人体肝脏新陈代谢中的反应方面的有效性。这种肝脏器官共培养系统为药物/化学品的代谢依赖性生物活性评估提供了一个实用的、更高通量的测试平台,可以更好地再现人体暴露的生物效应和潜在毒性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment.

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.

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来源期刊
Toxicological Sciences
Toxicological Sciences 医学-毒理学
CiteScore
7.70
自引率
7.90%
发文量
118
审稿时长
1.5 months
期刊介绍: The mission of Toxicological Sciences, the official journal of the Society of Toxicology, is to publish a broad spectrum of impactful research in the field of toxicology. The primary focus of Toxicological Sciences is on original research articles. The journal also provides expert insight via contemporary and systematic reviews, as well as forum articles and editorial content that addresses important topics in the field. The scope of Toxicological Sciences is focused on a broad spectrum of impactful toxicological research that will advance the multidisciplinary field of toxicology ranging from basic research to model development and application, and decision making. Submissions will include diverse technologies and approaches including, but not limited to: bioinformatics and computational biology, biochemistry, exposure science, histopathology, mass spectrometry, molecular biology, population-based sciences, tissue and cell-based systems, and whole-animal studies. Integrative approaches that combine realistic exposure scenarios with impactful analyses that move the field forward are encouraged.
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