Nephron progenitor cells (NPCs) are thought to undergo a linear progression from an uncommitted to a fully committed state as they move from the top of the cap mesenchyme to the junction between the tip and stalk of the ureteric epithelium where nephron formation occurs. Now, Alexander Combes, Melissa Little, Kynan Lawlor and colleagues report that not all NPCs that express commitment genes immediately form nephrons.

“We previously showed that the cap mesenchyme behaves like a randomly moving swarm,” says Combes. “Our current study attempts to understand how NPCs can exist as a randomly moving population but simultaneously undergo commitment to form nephrons at defined sites.”

As Wnt4 is one of the earliest known markers of progenitor commitment, the researchers used Wnt4 lineage tracing, live microscopy and single-cell RNA sequencing to investigate NPC differentiation in mice. They report that most NPCs that express Wnt4 commit to nephron formation but a small proportion “escape” commitment and migrate back into the uncommitted population, where they are able to return to a progenitor-like state.

These findings were consistent with a computer simulation in which commitment occurred in response to a spatially restricted induction signal in a motile progenitor population. “Cells that reached a certain threshold of induction signal committed, but those that moved away before this threshold was reached could return to the uncommitted population,” explains Lawlor.

“Having a stochastic element to commitment may be an efficient and simple way to maintain a progenitor population that is constantly moving but simultaneously giving rise to committed cells at a precise location,” suggests Combes. “This mechanism may be important to maintain the reciprocal signalling between the nephron progenitors and underlying tip that drives kidney growth through branching morphogenesis.”