Cystogenesis is a morphological consequence of numerous genetic diseases of the epithelium. In the kidney, the pathogenic mechanisms underlying the program of altered cell and tubule morphology are obscured by secondary effects of cyst expansion. Here, we developed a new 3D tubuloid system to isolate the rapid changes in protein localization and gene expression that correlate with altered cell and tubule morphology during cyst initiation. Mouse renal tubule fragments were pulsed with a cell differentiation cocktail including glial-derived neurotrophic factor (GDNF) to yield collecting duct-like tubuloid structures with appropriate polarity, primary cilia, and gene expression. Using the 3D tubuloid model with an inducible Pkd2 knockout system allowed the tracking of morphological, protein, and genetic changes during cyst formation. Within hours of inactivation of Pkd2 and loss of polycystin-2, we observed significant progression in tubuloid to cyst morphology that correlated with 35 differentially expressed genes, many related to cell junctions, matrix interactions, and cell morphology previously implicated in cystogenesis.This article has an associated First Person interview with the first author of the paper.

中文翻译：

---

GDNF 在 ADPKD 的新型 3D 体外模型中驱动快速肾小管形态发生。

囊肿发生是许多上皮遗传疾病的形态学结果。在肾脏中，细胞和肾小管形态改变程序背后的致病机制被囊肿扩张的继发效应所掩盖。在这里，我们开发了一种新的 3D 小管系统，以分离与囊肿起始过程中细胞和小管形态改变相关的蛋白质定位和基因表达的快速变化。用包含胶质源性神经营养因子 (GDNF) 的细胞分化混合物脉冲小鼠肾小管片段，以产生具有适当极性、初级纤毛和基因表达的集合管样管状结构。使用具有诱导型 Pkd2 敲除系统的 3D 管状模型可以跟踪囊肿形成过程中的形态、蛋白质和遗传变化。在 Pkd2 失活和多囊蛋白-2 丢失的数小时内，我们观察到管状到囊肿形态的显着进展，这与 35 个差异表达基因相关，其中许多与细胞连接、基质相互作用和先前与囊肿发生有关的细胞形态有关。对论文第一作者的相关第一人称采访。