Division of Pharmacology, National Institute of Health Sciences, Kanagawa, Japan; Pharmacological Evaluation Institute of Japan (PEIJ), Kanagawa, Japan.
Division of Pharmacology, National Institute of Health Sciences, Kanagawa, Japan.
J Pharmacol Sci. 2019 Aug;140(4):337-344. doi: 10.1016/j.jphs.2019.06.012. Epub 2019 Jul 26.
Vitamin A (VA) is a fat-soluble micronutrient that plays essential roles in various biological processes, including cell growth, differentiation, and apoptosis. In the intestine, VA are known to promote mucosal homeostasis and immunity. However, the effect of VA in intestinal development has not been well elucidated. In the present study, we generated human intestine organoids from human induced pluripotent stem cells (iPSCs), and investigated the effect of the VA active metabolite all-trans retinoic acid (RA), on differentiation into intestinal organoids. As a result, RA increased the gene expression of a drug-metabolizing enzyme CYP3A4, as a functional molecule of intestinal mature development, in iPSC-derived intestinal organoids. In addition, RA increased transepithelial electrical resistance, an indicator of epithelial integrity, and decreased the permeability of monolayers to fluorescein isothiocyanate-labeled dextran in intestinal epithelial monolayers. Finally, RA increased the expression of ZO-1, a marker of tight junctions, which are essential for intestinal epithelial barrier function. Taken together, these results indicate that RA promotes barrier functions of iPSC-derived intestinal epithelial monolayers by increasing ZO-1 expression.
维生素 A（VA）是一种脂溶性微量营养素，在细胞生长、分化和凋亡等各种生物过程中发挥着重要作用。在肠道中，VA 被认为能促进黏膜稳态和免疫。然而，VA 对肠道发育的影响尚未得到很好的阐明。在本研究中，我们从人诱导多能干细胞（iPSCs）中生成了人类肠道类器官，并研究了维生素 A 活性代谢产物全反式视黄酸（RA）对肠道类器官分化的影响。结果表明，RA 增加了 iPSC 衍生的肠道类器官中药物代谢酶 CYP3A4 的基因表达，CYP3A4 是肠道成熟发育的功能分子。此外，RA 增加了跨上皮电阻，这是上皮完整性的一个指标，并降低了肠道上皮单层对荧光素异硫氰酸酯标记的葡聚糖的通透性。最后，RA 增加了紧密连接标记物 ZO-1 的表达，这对于肠道上皮屏障功能至关重要。综上所述，这些结果表明，RA 通过增加 ZO-1 的表达促进 iPSC 衍生的肠道上皮单层的屏障功能。
