Abstract
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.
Highlights
Tissue stem cells maintain their numbers while continuously producing distinct types of differentiated cells (Morrison et al, 1997; Crosnier et al, 2006; van der Flier & Clevers, 2009; Clevers, 2013)
We demonstrate that efficient homeostatic mechanisms, involving Delta-Notch lateral inhibition that is restricted to a confined commitment zone, as well as dispersive goblet cell migration, buffer this variability
The system is composed of a cylindrical hexagonal lattice with three compartments—a stem cells (SCs) compartment comprised of a single row of 8 SCs, intermingled with 8 non-dividing niche cells representing deep secretory cells (Rothenberg et al, 2012), six rows of proliferating progenitors, and 15 rows of post-mitotic cells
Summary
Tissue stem cells maintain their numbers while continuously producing distinct types of differentiated cells (Morrison et al, 1997; Crosnier et al, 2006; van der Flier & Clevers, 2009; Clevers, 2013). These cell types often need to be produced at optimally tuned proportions. The mouse intestine is a classic model system for studying tissue stem cell processes. The epithelium of both the small intestine and the large intestine (colon) consists of deep invaginations called crypts. Secretory cells predominantly consist of goblet cells that secrete mucus, a key protective barrier against pathogens and mechanical stress (Atuma et al, 2001; Deplancke & Gaskins, 2001; Kim & Ho, 2010)
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