New gene editing technique turns human pluripotent stem cells into a model system for polycystic kidney disease

PKD's hallmark is the formation of damaging, balloon-like cysts in kidney tubules. In the early 2000s, cell biologists linked cyst formation to gene mutations that affect the primary cilia, hair-like projections from cells that seem to act as sensory antennae. These fundamental discoveries were made in non-human organisms such as the algae, Chlamydomonas reinhardtii, and the zebrafish, Danio rerio. But the exact disease mechanism in humans is still not well understood in part because there hasn't been a good human model of PKD in kidney cells.

CRISPR gave Freedman et al. a more precise tool to remodel the hPSC genome to include PKD mutations in the disease-linked genes, PKD1 and PKD2. The researchers then used a 3-D cell culture system to coax their mutant and healthy hPSCs down the differentiation pathway into becoming kidney progenitor cells and finally the proximal tubule cells found in kidney nephrons. In the mutant tubule cells, they observed the formation of large, translucent cyst-like structures but not in their healthy controls. These observations and others have convinced the researchers that their CRISPR/Cas9 and hPSC system produces a stable, biologically accurate human model for a common genetic disease where new understanding and new therapies are desperately needed.