Cell cycle criticality as a mechanism for robust cell population control

Abstract

Tissue homeostasis requires a precise balance between cellular self-renewal and differentiation. While fate decisions are known to be closely linked to cell cycle progression, the functional significance of this relationship is unclear. Here, we develop a mechanistic framework to analyse cellular dynamics when cell fate is coupled to cell cycle length. We focus on a distinct feature of cell cycle regulation where mitogens act as control parameters for a bifurcation governing the G1-S transition. Under competitive feedback from cell-cell interactions, the cell cycle regulatory network fine-tunes to the critical point of this bifurcation, becoming highly sensitive to mitogenic signalling. This critical positioning lengthens G1 while amplifying cell-to-cell variability in signalling and biochemical states. Such regulation confers significant advantages for controlling cell population dynamics, including maintaining a robust population set-point and rejecting mis-sensing mutants. The mutant rejection capability trades off against tissue growth and repair. Counter-intuitively, we propose that adult stem cells couple prolonged G1 with increased self-renewal propensity to efficiently eliminate mis-sensing mutants. Our theory explains and predicts regulatory patterns across development, homeostasis, and ageing.