A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery

Cell Stem Cell. 2022 Jul 7;29(7):1083-1101.e7. doi: 10.1016/j.stem.2022.06.005.

Abstract

Human pluripotent stem-cell-derived organoids are models for human development and disease. We report a modified human kidney organoid system that generates thousands of similar organoids, each consisting of 1-2 nephron-like structures. Single-cell transcriptomic profiling and immunofluorescence validation highlighted patterned nephron-like structures utilizing similar pathways, with distinct morphogenesis, to human nephrogenesis. To examine this platform for therapeutic screening, the polycystic kidney disease genes PKD1 and PKD2 were inactivated by gene editing. PKD1 and PKD2 mutant models exhibited efficient and reproducible cyst formation. Cystic outgrowths could be propagated for months to centimeter-sized cysts. To shed new light on cystogenesis, 247 protein kinase inhibitors (PKIs) were screened in a live imaging assay identifying compounds blocking cyst formation but not overall organoid growth. Scaling and further development of the organoid platform will enable a broader capability for kidney disease modeling and high-throughput drug screens.

Keywords: developmental trajectory; disease modeling; drug screen; high throughput; kidney development; kidney organoid; nephron development; phenotypic screen; polycystic kidney disease; scRNA-seq.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cysts* / metabolism
  • Drug Discovery
  • Humans
  • Kidney / metabolism
  • Organoids / metabolism
  • Polycystic Kidney, Autosomal Dominant* / drug therapy
  • Polycystic Kidney, Autosomal Dominant* / genetics
  • Polycystic Kidney, Autosomal Dominant* / metabolism
  • TRPP Cation Channels / genetics
  • TRPP Cation Channels / metabolism

Substances

  • TRPP Cation Channels