Authors: Shohei Kuraoka, Shunsuke Tanigawa, Atsuhiro Taguchi, Akitsu Hotta, Hitoshi Nakazato, Kenji Osafune, Akio Kobayashi, Ryuichi Nishinakamura
Summary: Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease leading to renal failure, wherein multiple cysts are formed in renal tubules and collecting ducts derived from distinct precursors: the nephron progenitor and ureteric bud (UB), respectively. Recent progress in induced pluripotent stem cell (iPSC) biology has enabled cyst formation in nephron progenitor-derived human kidney organoids lacking PKD1 and PKD2, the major causative genes for ADPKD. However, cyst formation in UB organoids has not been achieved, despite the prevalence of collecting duct cysts in ADPKD patients.
Methods: We deleted PKD1 in human iPSCs using CRISPR-Cas9 technology and differentially induced the cells toward nephron or UB organoids. We then investigated cyst formation in both types of kidney organoid. We also examined cyst formation in UB organoids generated from ADPKD patient-derived iPSCs.
Results: As observed in nephron organoids, cysts were formed in UB organoids with homozygous PKD1 mutations upon cAMP stimulation, and to a lesser extent, in heterozygous mutant organoids. Furthermore, UB organoids generated from ADPKD patient-derived iPSCs with a heterozygous missense mutation showed cystogenesis upon cAMP stimulation.
Conclusions: We demonstrated cyst formation in PKD1 mutant UB organoids, as well as those derived from an ADPKD patient. Our findings will serve as a valuable basis for elucidating the mechanisms of ADPKD.
Source: Journal of the American Society of Nephrology, 2020