RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan.
Laboratory of Molecular Cell Biology and Development, Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan.
Commun Biol. 2024 Nov 27;7(1):1532. doi: 10.1038/s42003-024-07069-6.
Human pluripotent stem cell-derived kidney organoids are expected to be a useful tool for new drug discoveries, however, the immaturation of kidney organoids causes difficulties in recapitulating renal pharmacokinetics using organoids. Here, we performed time-course single-cell RNA sequencing of kidney organoids and revealed cell heterogeneity in the maturation rate of the proximal tubule. An unbiased analysis to identify upstream targets of genes that are expressed differentially between cells with low and high maturation rates revealed a higher activation of PPARα signaling in rapidly maturing cells. Treatment with a combination of a PPARα agonist and an RXRα agonist induced genes related to proximal tubule maturation and increased the capacity for protein uptake as well as the sensitivity to nephrotoxicity by cisplatin. This method to promote the maturation rate of proximal tubule cells has the potential to be utilized in microphysiological systems to recapitulate proximal tubule functions and to screen nephrotoxic drugs.
人多能干细胞衍生的肾类器官有望成为新药发现的有用工具，然而，肾类器官的不成熟导致使用类器官重现肾药代动力学存在困难。在这里，我们对肾类器官进行了时间过程单细胞 RNA 测序，揭示了近端小管成熟率的细胞异质性。一种识别表达低成熟率和高成熟率细胞之间差异基因的上游靶点的无偏分析表明，快速成熟细胞中 PPARα 信号的激活更高。用 PPARα 激动剂和 RXRα 激动剂的组合处理诱导与近端小管成熟相关的基因，并增加了摄取蛋白质的能力以及对顺铂的肾毒性的敏感性。这种促进近端小管细胞成熟率的方法有可能在微生理系统中用于重现近端小管功能和筛选肾毒性药物。
