Plasticity of distal nephron epithelia from human kidney organoids enables the induction of ureteric tip and stalk

During development, distinct progenitors contribute to the nephrons versus the ureteric epithelium of the kidney. Indeed, previous human pluripotent stem-cell-derived models of kidney tissue either contain nephrons or pattern specifically to the ureteric epithelium. By re-analyzing the transcriptional distinction between distal nephron and ureteric epithelium in human fetal kidney, we show here that, while existing nephron-containing kidney organoids contain distal nephron epithelium and no ureteric epithelium, this distal nephron segment alone displays significant in vitro plasticity and can adopt a ureteric epithelial tip identity when isolated and cultured in defined conditions. “Induced” ureteric epithelium cultures can be cryopreserved, serially passaged without loss of identity, and transitioned toward a collecting duct fate. Cultures harboring loss-of-function mutations in PKHD1 also recapitulate the cystic phenotype associated with autosomal recessive polycystic kidney disease. [Display omitted] •Accurate prediction of cell identity within human kidney organoids•Evidence of distal nephron-specific epithelial plasticity•Ureteric epithelium induced from distal nephron can be cultured and expanded in vitro•Modeling of autosomal recessive polycystic kidney disease Little and colleagues demonstrate the plasticity of the distal nephron epithelium present within kidney organoids, showing that this can be induced to adopt a ureteric epithelial phenotype. Subsequent maturation of this epithelium generated collecting ducts, facilitating the accurate modeling of autosomal recessive polycystic kidney disease.