Interplay between substrate rigidity and tissue fluidity regulates cell monolayer spreading.

Abstract

Coordinated and cooperative motion of cells is essential for embryonic development, tissue morphogenesis, wound healing and cancer invasion. A predictive understanding of the emergent mechanical behaviors in collective cell motion is challenging due to the complex interplay between cell-cell interactions, cell-matrix adhesions and active cell behaviors. To overcome this challenge, we develop a predictive cellular vertex model that can delineate the relative roles of substrate rigidity, tissue mechanics and active cell properties on the movement of cell collectives. We apply the model to the specific case of collective motion in cell aggregates as they spread into a two-dimensional cell monolayer adherent to a soft elastic matrix. Consistent with recent experiments, we find that substrate stiffness regulates the driving forces for the spreading of cellular monolayer, which can be pressure-driven or crawling-based depending on substrate rigidity. On soft substrates, cell monolayer spreading is driven by an active pressure due to the influx of cells coming from the aggregate, whereas on stiff substrates, cell spreading is driven primarily by active crawling forces. Our model predicts that cooperation of cell crawling and tissue pressure drives faster spreading, while the spreading rate is sensitive to the mechanical properties of the tissue. We find that solid tissues spread faster on stiff substrates, with spreading rate increasing with tissue tension. By contrast, the spreading of fluid tissues is independent of substrate stiffness and is slower than solid tissues. We compare our theoretical results with experimental results on traction force generation and spreading kinetics of cell monolayers, and provide new predictions on the role of tissue fluidity and substrate rigidity on collective cell motion.