Scarlat Alexandru, Trionfini Piera, Rizzo Paola, Conti Sara, Longaretti Lorena, Breno Matteo, Longhi Lorenzo, Xinaris Christodoulos, Remuzzi Giuseppe, Benigni Ariela, Tomasoni Susanna
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
Sci Rep. 2025 Mar 26;15(1):10375. doi: 10.1038/s41598-025-94855-9.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal genetic disease, with most patients carrying mutations in PKD1. The main feature is the formation of bilateral renal cysts, leading to end stage renal failure in a significant proportion of those affected. Despite recent advances made in understanding ADPKD, there are currently no effective curative therapies. The emergence of human induced pluripotent stem cell (hiPSC)-derived kidney disease models has led to renewed hope that more physiological systems will allow for the development of novel treatments. hiPSC-derived organoid models have been used to recapitulate ADPKD, however they present numerous limitations which remain to be addressed. In the present study, we report an efficient method for generating organoids containing a network of polarised and ciliated epithelial tubules. PKD1 null (PKD1) organoids spontaneously develop dilated tubules, recapitulating early ADPKD cystogenesis. Furthermore, PKD1 tubules present primary cilia defects when dilated. Our model could therefore serve as a valuable tool to study early ADPKD cystogenesis and to develop novel therapies.
常染色体显性多囊肾病（ADPKD）是最常见的肾脏遗传性疾病，大多数患者携带PKD1基因突变。其主要特征是双侧肾囊肿的形成，导致很大比例的患者发展为终末期肾衰竭。尽管最近在理解ADPKD方面取得了进展，但目前尚无有效的治愈性疗法。人诱导多能干细胞（hiPSC）衍生的肾脏疾病模型的出现，让人们重新燃起希望，即更多的生理系统将有助于开发新的治疗方法。hiPSC衍生的类器官模型已被用于模拟ADPKD，然而它们存在许多有待解决的局限性。在本研究中，我们报告了一种高效的方法来生成包含极化和纤毛上皮小管网络的类器官。PKD1基因敲除（PKD1）类器官会自发形成扩张的小管，模拟早期ADPKD囊肿形成。此外，PKD1小管在扩张时存在初级纤毛缺陷。因此，我们的模型可作为研究早期ADPKD囊肿形成和开发新疗法的宝贵工具。
