Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences (D.O., M.Y., A.N., T.H., T.I., T.M.), and Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (T.A., Y.K., I.O., T.H., T.I., T.M.), Nagoya City University, Nagoya, Japan.
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences (D.O., M.Y., A.N., T.H., T.I., T.M.), and Educational Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (T.A., Y.K., I.O., T.H., T.I., T.M.), Nagoya City University, Nagoya, Japan
Drug Metab Dispos. 2018 Nov;46(11):1572-1580. doi: 10.1124/dmd.118.080374. Epub 2018 Apr 3.
Intestinal organoids morphologically resemble intestinal tissues and are expected to be used in both regenerative medicine and drug development studies, including pharmacokinetic studies. However, the pharmacokinetic properties of these organoids remain poorly characterized. In this study, we aimed to generate pharmacokinetically functional intestinal organoids from human induced pluripotent stem (iPS) cells. Human iPS cells were induced to differentiate into the midgut and then seeded on EZSPHERE plates (AGC Techno Glass Inc., Shizuoka, Japan) to generate uniform spheroids, and the floating spheroids were subsequently differentiated into intestinal organoids using small-molecule compounds. Exposure to the small-molecule compounds potently increased the expression of intestinal markers and pharmacokinetic-related genes in the organoids, and the organoids also included various intestinal cells such as enterocytes, intestinal stem cells, goblet cells, enteroendocrine cells, Paneth cells, smooth muscle cells, and fibroblasts. Moreover, microvilli and tight junctions were observed in the organoids. Furthermore, we detected not only the expression of drug transporters but also efflux transport activity through ABCB1/MDR1 and the induction of the drug-metabolizing enzyme CYP3A4 by ligands of nuclear receptors. Our results demonstrated the successful generation of pharmacokinetically functional intestinal organoids from human iPS cells. Thus, these intestinal organoids could be used as a pharmacokinetic evaluation system in drug development studies.
肠类器官在形态上类似于肠组织，预计将被用于再生医学和药物开发研究，包括药代动力学研究。然而，这些类器官的药代动力学特性仍未得到很好的描述。在这项研究中，我们旨在从人诱导多能干细胞（iPS 细胞）中生成具有药代动力学功能的肠类器官。人 iPS 细胞被诱导分化为中肠，然后接种到 EZSPHERE 平板（AGC Techno Glass Inc.，静冈，日本）上以生成均匀的球体，然后使用小分子化合物将漂浮的球体分化为肠类器官。小分子化合物的暴露强烈增加了类器官中肠标志物和药代动力学相关基因的表达，并且类器官还包含各种肠细胞，如肠上皮细胞、肠干细胞、杯状细胞、肠内分泌细胞、潘氏细胞、平滑肌细胞和成纤维细胞。此外，在类器官中观察到微绒毛和紧密连接。此外，我们不仅检测到了药物转运体的表达，还检测到了通过 ABCB1/MDR1 的外排转运活性，以及核受体配体对药物代谢酶 CYP3A4 的诱导。我们的结果表明，从人 iPS 细胞中成功生成了具有药代动力学功能的肠类器官。因此，这些肠类器官可以用作药物开发研究中的药代动力学评价系统。
