PKD1-Dependent Renal Cystogenesis in Human Induced Pluripotent Stem Cell-Derived Ureteric Bud/Collecting Duct Organoids.
J Am Soc Nephrol
; 31(10): 2355-2371, 2020 10.
Article
in En
| MEDLINE
| ID: mdl-32747355
ABSTRACT
BACKGROUND:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease leading to renal failure, wherein multiple cysts form 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 in which PKD1 or PKD2, the major causative genes for ADPKD, are deleted. However, cysts have not been generated in UB organoids, despite the prevalence of collecting duct cysts in patients with ADPKD.METHODS:
CRISPR-Cas9 technology deleted PKD1 in human iPSCs and the cells induced to differentiate along pathways leading to formation of either nephron progenitor or UB organoids. Cyst formation was investigated in both types of kidney organoid derived from PKD1-deleted iPSCs and in UB organoids generated from iPSCs from a patient with ADPKD who had a missense mutation.RESULTS:
Cysts 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 iPSCs from a patient with ADPKD who had a heterozygous missense mutation developed cysts upon cAMP stimulation.CONCLUSIONS:
Cysts form in PKD1 mutant UB organoids as well as in iPSCs derived from a patient with ADPKD. The organoids provide a robust model of the genesis of ADPKD.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ureter
/
Organoids
/
Polycystic Kidney, Autosomal Dominant
/
TRPP Cation Channels
/
Induced Pluripotent Stem Cells
/
Nephrons
Type of study:
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
J Am Soc Nephrol
Journal subject:
NEFROLOGIA
Year:
2020
Document type:
Article
Affiliation country:
Japan