Mechanical control of cell proliferation patterns in growing epithelial monolayers

Abstract

Cell proliferation plays a crucial role in regulating tissue homeostasis and development. However, our understanding of how cell proliferation is controlled in densely packed tissues is limited. Here we develop a computational framework to predict the patterns of cell proliferation in growing epithelial tissues, connecting single-cell behaviors and cell-cell interactions to tissue-level growth. Our model incorporates probabilistic rules governing cell growth, division, and elimination, also taking into account their feedback with tissue mechanics. In particular, cell growth is suppressed and apoptosis is enhanced in regions of high cell density. With these rules and model parameters calibrated using experimental data for epithelial monolayers, we predict how tissue confinement influences cell size and proliferation dynamics and how single-cell physical properties influence the spatiotemporal patterns of tissue growth. In this model, mechanical feedback between tissue confinement and cell growth leads to enhanced cell proliferation at tissue boundaries, whereas cell growth in the bulk is arrested, recapitulating experimental observations in epithelial tissues. By tuning cellular elasticity and contact inhibition of proliferation we can regulate the emergent patterns of cell proliferation, ranging from uniform growth at low contact inhibition to localized growth at higher contact inhibition. We show that the cell size threshold at G1/S transition governs the homeostatic cell density and tissue turnover rate, whereas the mechanical state of the tissue governs the dynamics of tissue growth. In particular, we find that the cellular parameters affecting tissue pressure play a significant role in determining the overall growth rate. Our computational study thus underscores the impact of cell mechanical properties on the spatiotemporal patterns of cell proliferation in growing epithelial tissues.