학술논문
Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitroand in vivo
Document Type
Article
Author
Liu, Meng; Zhang, Chao; Gong, Ximing; Zhang, Tian; Lian, Michelle Mulan; Chew, Elaine Guo Yan; Cardilla, Angelysia; Suzuki, Keiichiro; Wang, Huamin; Yuan, Yuan; Li, Yan; Naik, Mihir Yogesh; Wang, Yixuan; Zhou, Bingrui; Soon, Wei Ze; Aizawa, Emi; Li, Pin; Low, Jian Hui; Tandiono, Moses; Montagud, Enrique; Moya–Rull, Daniel; Rodriguez Esteban, Concepcion; Luque, Yosu; Fang, Mingliang; Khor, Chiea Chuen; Montserrat, Nuria; Campistol, Josep M.; Izpisua Belmonte, Juan Carlos; Foo, Jia Nee; Xia, Yun
Source
Cell Stem Cell; January 2024, Vol. 31 Issue: 1 p52-70.e8
Subject
Language
ISSN
19345909
Abstract
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 in vitroand in vivoorganoid 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 in vivo. This in vivoorganoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.