Renal tubule epithelium undergoes cyst formation in numerous genetic diseases. The effects of subsequent cyst expansion hinders the elucidation of the pathogenic mechanisms that affect tubule morphology. To this end, in their ‘Tools and Resources’ article (Dixon et al., 2020), Eryn Dixon, Owen Woodward and colleagues have developed a 3D tubuloid system to capture changes at the molecular and morphological level during cyst initiation by culturing mouse renal tubule fragments in the presence of glial-derived neurotrophic factor (GDNF). Using this model, the authors were able to study one of the most prevalent genetic epithelial cystic diseases, autosomal dominant polycystic kidney disease (ADPKD), which is caused by loss-of-function mutations in PKD1 and PKD2 encoding polycystin-1 and -2. In contrast to other in vitro 3D models used to study cystogenesis in ADPKD, this new model makes it possible to observe morphological changes in an intact tubuloid. To model ADPKD, the authors utilised an inducible Pkd2-knockout system to induce cyst initiation, while at the same time tracking protein abundance, gene expression levels and morphological changes. Deletion of Pkd2 in the tubuloids differentially altered gene expression of 35 genes, with many of the associated proteins having been previously implicated in cystic phenotypes, thus validating the system. Taken together, this new in vitro 3D tubuloid system is a promising new approach to dissect the complicated pathogenesis of polycystic kidney disease.
