小柯机器人

新加坡南洋理工大学Yun Xia，Jia Nee Foo和美国Altos实验室Juan Carlos Izpisua共同合作，近期取得重要工作进展。他们通过研究肾脏类器官模型揭示纤毛-自噬代谢轴是PKD体外和体内的治疗靶点。相关研究成果2024年1月4日在线发表于《细胞—干细胞》杂志上。

据介绍，人类多能干细胞来源的肾脏类器官为研究多囊肾病（PKD）提供了前所未有的机会，但该疾病仍没有有效的治疗方法。

研究人员开发了PKD的体外和体内类器官模型，该模型表现为肾小管损伤和肾素-血管紧张素-醛固酮系统的异常上调。单细胞分析显示，膀胱发生过程中发生了无数的代谢变化，包括自噬缺陷。通过ATG5过表达或原发性纤毛消融的自噬实验激活显著抑制PKD肾类器官的膀胱生成。利用PKD的类器官异种移植物模型，研究人员证明了米诺地尔（一种强效的自噬激活剂，FDA批准的药物）能有效地减轻了体内囊肿的形成。

总之，这种PKD的体内类器官模型将增强研究人员发现新的疾病机制和临床评估候选药物的能力。

附：英文原文

Title: Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitro and in vivo

Author: Meng Liu, Chao Zhang, Ximing Gong, Tian Zhang, Michelle Mulan Lian, Elaine Guo Yan Chew, Angelysia Cardilla, Keiichiro Suzuki, Huamin Wang, Yuan Yuan, Yan Li, Mihir Yogesh Naik, Yixuan Wang, Bingrui Zhou, Wei Ze Soon, Emi Aizawa, Pin Li, Jian Hui Low, Moses Tandiono, Enrique Montagud, Daniel Moya–Rull, Concepcion Rodriguez Esteban, Yosu Luque, Mingliang Fang, Chiea Chuen Khor, Nuria Montserrat, Josep M. Campistol, Juan Carlos Izpisua Belmonte, Jia Nee Foo, Yun Xia

Issue&Volume: 2024/01/04

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

DOI: 10.1016/j.stem.2023.12.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00433-2

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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