Division of Nephrology, University of Washington School of Medicine, Seattle, Washington 98109, USA.
Kidney Research Institute, University of Washington School of Medicine, Seattle, Washington 98109, USA.
Nat Mater. 2017 Nov;16(11):1112-1119. doi: 10.1038/nmat4994. Epub 2017 Oct 2.
Polycystic kidney disease (PKD) is a life-threatening disorder, commonly caused by defects in polycystin-1 (PC1) or polycystin-2 (PC2), in which tubular epithelia form fluid-filled cysts. A major barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis. Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids. Here we show that systematic substitution of physical components can dramatically increase or decrease cyst formation, unveiling a critical role for microenvironment in PKD. Removal of adherent cues increases cystogenesis 10-fold, producing cysts phenotypically resembling PKD that expand massively to 1-centimetre diameters. Removal of stroma enables outgrowth of PKD cell lines, which exhibit defects in PC1 expression and collagen compaction. Cyclic adenosine monophosphate (cAMP), when added, induces cysts in both PKD organoids and controls. These biomaterials establish a highly efficient model of PKD cystogenesis that directly implicates the microenvironment at the earliest stages of the disease.
多囊肾病（PKD）是一种危及生命的疾病，通常由多囊蛋白-1（PC1）或多囊蛋白-2（PC2）的缺陷引起，在这种疾病中，管状上皮形成充满液体的囊肿。了解 PKD 的主要障碍是缺乏能够准确有效地重现囊肿发生的人类细胞模型。此前，我们已经使用人类多能干细胞和衍生的肾脏类器官生成了 PKD 的遗传模型。在这里，我们表明系统替代物理成分可以显著增加或减少囊肿的形成，揭示了微环境在 PKD 中的关键作用。去除黏附线索可使囊肿形成增加 10 倍，产生类似于 PKD 的囊肿，其体积迅速扩大至 1 厘米直径。去除基质可使 PKD 细胞系生长，这些细胞系表现出 PC1 表达和胶原紧缩缺陷。添加环磷酸腺苷（cAMP）可诱导 PKD 类器官和对照物中的囊肿。这些生物材料建立了一种高效的 PKD 囊肿发生模型，直接涉及疾病早期的微环境。
