Early commitment and robust differentiation in colonic crypts.

Tissue stem cells produce a constant flux of differentiated cells with distinct proportions. Here, we show that stem cells in colonic crypts differentiate early to form precisely 1:3 ratio of secretory to absorptive cells. This precision is surprising, as there are only eight stem cells making irreversible fate decisions, and so large stochastic effects of this small pool should have yielded much larger noise in cell proportions. We use single molecule FISH, lineage-tracing mice and simulations to identify the homeostatic mechanisms facilitating robust proportions. We find that Delta-Notch lateral inhibition operates in a restricted spatial zone to reduce initial noise in cell proportions. Increased dwell time and dispersive migration of secretory cells further averages additional variability added during progenitor divisions and breaks up continuous patches of same-fate cells. These noise-reducing mechanisms resolve the trade-off between early commitment and robust differentiation and ensure spatially uniform spread of secretory cells. Our findings may apply to other cases where small progenitor pools expand to give rise to precise tissue cell proportions.