Unraveling the Control of Cell Cycle Periods During Intestinal Stem Cell Differentiation

During differentiation, intestinal stem cells (ISCs), a prototypical adult stem cell pool, become either secretory transit-amplifying cells, which give rise to all secretory cell types, or absorptive transit-amplifying cells, which give rise to enterocytes. These cells exhibit distinct cell cycle dynamics: ISCs cycle with a period of 24 h and absorptive transit-amplifying cells cycle with a period of ∼12 h, whereas secretory transit-amplifying cells arrest their cycle. The cell cycle dynamics of ISCs and their progeny are a systems-level property that emerges from interactions between the cell cycle control machinery and multiple regulatory pathways. Although many mathematical models have been developed to study the details of the cell cycle and related regulatory pathways, few models have been constructed to unravel the dynamic consequences of their interactions. To fill this gap, we present a simplified model focusing on the interaction between four key regulatory pathways (STAT, Wnt, Notch, and MAPK) and cell cycle control. After experimentally validating a model prediction, which showed that the Notch pathway can fine-tune the cell cycle period, we perform further model analysis that reveals that the change of cell cycle period accompanying ISC differentiation may be controlled by a design principle that has been well studied in dynamical systems theory-a saddle node on invariant circle bifurcation. Given that the mechanisms that control the cell cycle are conserved in most eukaryotic cell types, this general principle potentially controls the interplay between proliferation and differentiation for a broad range of stem cells.