Exit from quiescence displays a memory of cell growth and division

Reactivating quiescent cells to proliferate is critical to tissue repair and homoeostasis. Quiescence exit is highly noisy even for genetically identical cells under the same environmental conditions. Deregulation of quiescence exit is associated with many diseases, but cellular mechanisms underlying the noisy process of exiting quiescence are poorly understood. Here we show that the heterogeneity of quiescence exit reflects a memory of preceding cell growth at quiescence induction and immediate division history before quiescence entry, and that such a memory is reflected in cell size at a coarse scale. The deterministic memory effects of preceding cell cycle, coupled with the stochastic dynamics of an Rb-E2F bistable switch, jointly and quantitatively explain quiescence-exit heterogeneity. As such, quiescence can be defined as a distinct state outside of the cell cycle while displaying a sequential cell order reflecting preceding cell growth and division variations.