Murdoch Children's Research Institute, Flemington Rd, Parkville, VIC, Australia.
Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia.
Nat Commun. 2022 Oct 8;13(1):5943. doi: 10.1038/s41467-022-33623-z.
While pluripotent stem cell-derived kidney organoids are now being used to model renal disease, the proximal nephron remains immature with limited evidence for key functional solute channels. This may reflect early mispatterning of the nephrogenic mesenchyme and/or insufficient maturation. Here we show that enhanced specification to metanephric nephron progenitors results in elongated and radially aligned proximalised nephrons with distinct S1 - S3 proximal tubule cell types. Such PT-enhanced organoids possess improved albumin and organic cation uptake, appropriate KIM-1 upregulation in response to cisplatin, and improved expression of SARS-CoV-2 entry factors resulting in increased viral replication. The striking proximo-distal orientation of nephrons resulted from localized WNT antagonism originating from the organoid stromal core. PT-enhanced organoids represent an improved model to study inherited and acquired proximal tubular disease as well as drug and viral responses.
虽然多能干细胞衍生的肾类器官现在被用于模拟肾脏疾病,但近端肾单位仍然不成熟,关键功能溶质通道的证据有限。这可能反映了肾祖细胞的早期错误模式和/或成熟不足。在这里,我们表明增强向后肾原基祖细胞的特化会导致近端肾小管伸长和径向排列,并具有明显的 S1-S3 近端小管细胞类型。这种增强的 PT 类器官具有改善的白蛋白和有机阳离子摄取能力,对顺铂的适当 KIM-1 上调,以及改善的 SARS-CoV-2 进入因子的表达,从而导致病毒复制增加。肾单位的显著近-远轴定向是由于类器官基质核心中局部 WNT 拮抗作用引起的。PT 增强的类器官代表了一种改进的模型,可用于研究遗传性和获得性近端肾小管疾病以及药物和病毒反应。