Stable and robust differentiation programs are predominantly irreversible

Multicellular differentiation programs are almost always irreversible, with cells rarely revisiting states observed during earlier developmental stages. An important factor contributing to such irreversibility may be the cellular context: the dependence of each cells fate decisions on inductive signals from other, simultaneously present cell types. Using a class of rule-based models for context-dependent cell fate decisions we examine the evolutionary basis for the observed prevalence of irreversibility. Our study suggests that irreversibility, instead of being directly selected for, could be widespread due to its association with two other key traits, stability and robustness, which are essential for reproducible, cancer-free organismal formation. We identify further structural properties of desirable fate-decision programs and illustrate how explicit knowledge of cellular context is required for predicting developmental outcomes.