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

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
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, Yun Xia
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引用次数: 0

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 vitro and in vivo 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 in vivo. This in vivo organoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.

Abstract Image

肾脏类器官模型揭示了纤毛-自噬代谢轴在体外和体内都是 PKD 的治疗靶点
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,目前仍无有效的治疗方法。在这里,我们建立了PKD的体外和体内类器官模型,这些模型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,在膀胱生成过程中发生了大量代谢变化,包括自噬缺陷。通过ATG5过表达或原发性纤毛消融来激活自噬的实验方法显著抑制了PKD肾脏器官组织的囊肿生成。利用自发形成肾小管囊肿的 PKD 器官异种移植模型,我们证明米诺地尔(一种强效自噬激活剂,也是美国食品与药物管理局批准的药物)能有效抑制囊肿在体内的形成。这种 PKD 体内类器官模型将提高我们发现新型疾病机制和验证候选药物临床转化的能力。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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