The gastrointestinal tract is the most common exposure route of xenobiotics, and intestinal toxicity can result in systemic toxicity in most cases. It is important to develop intestinal toxicity assays mimicking the human system; thus, stem cells are rapidly being developed as new paradigms of toxicity assessment. In this study, we established human embryonic stem cell (hESC)-derived enterocyte-like cells (ELCs) and compared them to existing in vivo and in vitro models. We found that hESC-ELCs and the in vivo model showed transcriptomically similar expression patterns of a total of 10,020 genes than the commercialized cell lines. Besides, we treated the hESC-ELCs, in vivo rats, Caco-2 cells, and Hutu-80 cells with quarter log units of lethal dose 50 or lethal concentration 50 of eight drugs—chloramphenicol, cycloheximide, cytarabine, diclofenac, fluorouracil, indomethacin, methotrexate, and oxytetracycline—and then subsequently analyzed the biomolecular markers and morphological changes. While the four models showed similar tendencies in general toxicological reaction, hESC-ELCs showed a stronger correlation with the in vivo model than the immortalized cell lines. These results indicate that hESC-ELCs can serve as a next-generation intestinal toxicity model.

胃肠道是外源性物质最常见的暴露途径，肠道毒性在大多数情况下可导致全身毒性。开发模拟人体系统的肠道毒性试验很重要；因此，干细胞正在迅速发展成为毒性评估的新范例。在这项研究中，我们建立了人胚胎干细胞 (hESC) 衍生的肠细胞样细胞 (ELC) 并将它们与现有的体内 和 体外楷模。我们发现 hESC-ELCs 和体内模型显示了与商业化细胞系相比，总共 10,020 个基因在转录组学上相似的表达模式。此外，我们处理了 hESC-ELC，体内用氯霉素、放线菌酮、阿糖胞苷、双氯芬酸、氟尿嘧啶、吲哚美辛、甲氨蝶呤和土霉素等八种药物的致死剂量 50 或致死浓度 50 的四分之一对数单位对大鼠、Caco-2 细胞和 Hutu-80 细胞进行分析，然后分析了生物分子标记和形态变化。虽然四种模型在一般毒理学反应中表现出相似的趋势，但 hESC-ELC 与体内模型比永生化细胞系。这些结果表明 hESC-ELCs 可以作为下一代肠道毒性模型。