2022年7月7日出版的《细胞—干细胞》杂志发表了美国科学家的一项最新研究成果。来自南加州大学的Andrew P. McMahon研究小组表明，人类常染色体显性多囊肾病的可扩展类器官模型可用于疾病机制和药物发现。

研究人员报告了一个改良的人类肾脏类器官系统，该系统产生了数千个类似的类器官，每个类器官由1-2个肾脏结构组成。单细胞转录组分析和免疫荧光验证突出了利用类似途径的模式化肾脏样结构，其形态发生与人类的肾脏发生不同。为了研究这个平台的治疗筛选，研究人员通过基因编辑使多囊肾病基因PKD1和PKD2失活。PKD1和PKD2突变体模型表现出高效和可重复的囊肿形成。囊肿外植体可以在几个月内繁殖到厘米大小的囊肿。

为了揭示囊肿形成的新情况，研究人员在活体成像实验中筛选了247种蛋白激酶抑制剂（PKI），并确定了阻断囊肿形成但不阻断整体类器官生长的化合物。类器官平台的扩展和进一步发展将使肾脏疾病建模和高通量药物筛选的能力更加广泛。

据了解，人类多能干细胞衍生的器官是人类发育和疾病的模型。

附：英文原文

Title: A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery

Author: Tracy Tran, Cheng Jack Song, Trang Nguyen, Shun-Yang Cheng, Jill A. McMahon, Rui Yang, Qiuyu Guo, Balint Der, Nils O. Lindstrm, Daniel C.-H. Lin, Andrew P. McMahon

Issue&Volume: 2022/07/07

Abstract: Human pluripotent stem-cell-derived organoids are models for human development and disease. We report a modified human kidney organoid system that generates thousands of similar organoids, each consisting of 1–2 nephron-like structures. Single-cell transcriptomic profiling and immunofluorescence validation highlighted patterned nephron-like structures utilizing similar pathways, with distinct morphogenesis, to human nephrogenesis. To examine this platform for therapeutic screening, the polycystic kidney disease genes PKD1 and PKD2 were inactivated by gene editing. PKD1 and PKD2 mutant models exhibited efficient and reproducible cyst formation. Cystic outgrowths could be propagated for months to centimeter-sized cysts. To shed new light on cystogenesis, 247 protein kinase inhibitors (PKIs) were screened in a live imaging assay identifying compounds blocking cyst formation but not overall organoid growth. Scaling and further development of the organoid platform will enable a broader capability for kidney disease modeling and high-throughput drug screens.

DOI: 10.1016/j.stem.2022.06.005

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00254-5