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Direct transcriptomic comparison of xenobiotic metabolism and toxicity pathway induction of airway epithelium models at an air–liquid interface generated from induced pluripotent stem cells and primary bronchial epithelial cells
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-05-31 , DOI: 10.1007/s10565-022-09726-0
Ivo Djidrovski 1, 2 , Maria Georgiou 2 , Elena Tasinato 1 , Martin O Leonard 3 , Jelle Van den Bor 4 , Majlinda Lako 2 , Lyle Armstrong 1, 2
Affiliation  

Abstract

The airway epithelium represents the main barrier between inhaled air and the tissues of the respiratory tract and is therefore an important point of contact with xenobiotic substances into the human body. Several studies have recently shown that in vitro models of the airway grown at an air–liquid interface (ALI) can be particularly useful to obtain mechanistic information about the toxicity of chemical compounds. However, such methods are not very amenable to high throughput since the primary cells cannot be expanded indefinitely in culture to obtain a sustainable number of cells. Induced pluripotent stem cells (iPSCs) have become a popular option in the recent years for modelling the airways of the lung, but despite progress in the field, such models have so far not been assessed for their ability to metabolise xenobiotic compounds and how they compare to the primary bronchial airway model (pBAE). Here, we report a comparative analysis by TempoSeq (oligo-directed sequencing) of an iPSC-derived airway model (iBAE) with a primary bronchial airway model (pBAE). The iBAE and pBAE were differentiated at an ALI and then evaluated in a 5-compound screen with exposure to a sub-lethal concentration of each compound for 24 h. We found that despite lower expression of xenobiotic metabolism genes, the iBAE similarly predicted the toxic pathways when compared to the pBAE model. Our results show that iPSC airway models at ALI show promise for inhalation toxicity assessments with further development.

Graphical abstract



中文翻译:

由诱导多能干细胞和原代支气管上皮细胞产生的气液界面上气道上皮模型的异生物质代谢和毒性途径诱导的直接转录组学比较

摘要

气道上皮细胞是吸入空气和呼吸道组织之间的主要屏障,因此是异生物质进入人体的重要接触点。最近的几项研究表明,在气液界面 (ALI) 生长的气道体外模型对于获取有关化合物毒性的机理信息特别有用。然而,此类方法不太适合高通量,因为原代细胞不能在培养物中无限期扩增以获得可持续数量的细胞。近年来,诱导多能干细胞 (iPSC) 已成为肺气道建模的流行选择,但尽管该领域取得了进展,到目前为止,尚未评估此类模型代谢异生化合物的能力以及它们与初级支气管气道模型 (pBAE) 的比较情况。在这里,我们报告了通过 TempoSeq(寡核苷酸定向测序)对 iPSC 衍生气道模型 (iBAE) 与初级支气管气道模型 (pBAE) 进行的比较分析。iBAE 和 pBAE 在 ALI 中进行区分,然后在暴露于亚致死浓度的每种化合物 24 小时的 5 种化合物筛选中进行评估。我们发现,尽管异源代谢基因的表达较低,但与 pBAE 模型相比,iBAE 类似地预测了毒性途径。我们的结果表明,ALI 的 iPSC 气道模型显示了进一步开发吸入毒性评估的前景。我们报告了通过 TempoSeq(寡核苷酸定向测序)对 iPSC 衍生气道模型 (iBAE) 与初级支气管气道模型 (pBAE) 进行的比较分析。iBAE 和 pBAE 在 ALI 中进行区分,然后在暴露于亚致死浓度的每种化合物 24 小时的 5 种化合物筛选中进行评估。我们发现,尽管异源代谢基因的表达较低,但与 pBAE 模型相比,iBAE 类似地预测了毒性途径。我们的结果表明,ALI 的 iPSC 气道模型显示了进一步开发吸入毒性评估的前景。我们报告了通过 TempoSeq(寡核苷酸定向测序)对 iPSC 衍生气道模型 (iBAE) 与初级支气管气道模型 (pBAE) 进行的比较分析。iBAE 和 pBAE 在 ALI 中进行区分,然后在暴露于亚致死浓度的每种化合物 24 小时的 5 种化合物筛选中进行评估。我们发现,尽管异源代谢基因的表达较低,但与 pBAE 模型相比,iBAE 类似地预测了毒性途径。我们的结果表明,ALI 的 iPSC 气道模型显示了进一步开发吸入毒性评估的前景。iBAE 和 pBAE 在 ALI 中进行区分,然后在暴露于亚致死浓度的每种化合物 24 小时的 5 种化合物筛选中进行评估。我们发现,尽管异源代谢基因的表达较低,但与 pBAE 模型相比,iBAE 类似地预测了毒性途径。我们的结果表明,ALI 的 iPSC 气道模型显示了进一步开发吸入毒性评估的前景。iBAE 和 pBAE 在 ALI 中进行区分,然后在暴露于亚致死浓度的每种化合物 24 小时的 5 种化合物筛选中进行评估。我们发现,尽管异源代谢基因的表达较低,但与 pBAE 模型相比,iBAE 类似地预测了毒性途径。我们的结果表明,ALI 的 iPSC 气道模型显示了进一步开发吸入毒性评估的前景。

图形概要

更新日期:2022-06-01
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