Human pluripotent stem cell-derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both and organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single-cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent autophagy activator and an FDA-approved drug, effectively attenuated cyst formation . This organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.

中文翻译：

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肾脏类器官模型揭示纤毛自噬代谢轴作为 PKD 体外和体内治疗靶点

人类多能干细胞衍生的肾脏类器官为研究多囊肾病（PKD）提供了前所未有的机会，目前该病仍无法有效治愈。在这里，我们开发了 PKD 的类器官模型，其表现出肾小管损伤和肾素-血管紧张素醛固酮系统的异常上调。单细胞分析表明，在囊肿发生过程中发生了无数代谢变化，包括有缺陷的自噬。通过 ATG5 过表达或初级纤毛消融实验性激活自噬可显着抑制 PKD 肾类器官的囊肿发生。采用自发形成管状囊肿的 PKD 类器官异种移植模型，我们证明米诺地尔（一种有效的自噬激活剂和 FDA 批准的药物）可以有效减弱囊肿的形成。这种 PKD 类器官模型将增强我们发现新疾病机制和验证临床转化候选药物的能力。