Cell Stem Cell
Volume 29, Issue 7, 7 July 2022, Pages 1083-1101.e7
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Article
A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery

https://doi.org/10.1016/j.stem.2022.06.005Get rights and content
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Highlights

  • Scalable human kidney organoid platform with 1–2 nephron-like structures/organoid

  • Comparative scRNA-seq profiling of in vivo and in vitro kidney programs

  • PKD1 and PKD2 mutant kidney organoids display efficient cyst formation

  • Identification of cyst-inhibitory compounds from small-molecule screens

Summary

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

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

Cited by (0)

3

Present address: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA

4

Present address: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA

5

Present address: 23andMe, 349 Oyster Point Blvd, South San Francisco, CA 94080, USA

6

These authors contributed equally

7

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