Cell cycle criticality as a mechanism for robust cell population control.

Abstract

Tissue homeostasis requires a precise balance between stem cell self-renewal and differentiation. While fate decisions are known to be closely linked with cell cycle progression, the functional significance of this relationship is unclear. We propose a mechanistic framework to analyse cellular dynamics when cell fate is coupled to cell cycle duration. Our model highlights a unique aspect of cell cycle regulation where mitogens serve 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 near the critical point of this bifurcation. Critical positioning lengthens G1 while amplifying cell-to-cell variability in mitogenic signalling and biochemical states. Such regulation confers significant advantages for controlling cell population dynamics, with alternative topologies enabling rapid tissue growth and repair or efficient mutant rejection. Counter-intuitively, we propose that stem cells may couple prolonged G1 with increased self-renewal propensity to efficiently suppress mis-sensing mutants. Our theory provides a distinct explanation to dynamical and statistical patterns of G1 lengthening and predicts regulatory strategies across development, homeostasis, and ageing.