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^1,2. A major barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis^3,4. Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids^5,6. 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.

多囊肾疾病（PKD）是一种威胁生命的疾病，通常由多囊蛋白1（PC1）或多囊蛋白2（PC2）的缺陷引起，其中肾小管上皮形成充满液体的囊肿^1,2。理解PKD的主要障碍是缺乏能够准确有效地概括囊肿发生^3,4的人类细胞模型。以前，我们已经使用人类多能干细胞和衍生的肾脏类器官^5,6建立了PKD的遗传模型。。在这里，我们证明了物理成分的系统替代可以显着增加或减少囊肿的形成，从而揭示了微环境在PKD中的关键作用。去除附着的提示会增加10倍的囊肿发生，产生与PKD在表型上相似的囊肿，该囊肿可大量扩张至1厘米的直径。去除基质可以使PKD细胞系向外生长，而PKD细胞系在PC1表达和胶原蛋白紧缩中表现出缺陷。当添加环磷酸一腺苷（cAMP）时，会在PKD类器官和对照中诱导囊肿。这些生物材料建立了PKD囊肿发生的高效模型，该模型直接牵涉疾病早期的微环境。