Multiscale modelling shows how cell-ECM interactions impact ECM fibre alignment and cell detachment

Abstract

The extracellular matrix (ECM) is a dynamic network structure that surrounds, supports, and influences cell behaviour. It facilitates cell communication and plays an important role in cell functions such as growth and migration. One way that cells interact with the ECM is via focal adhesions, which enable them to sense and respond to matrix mechanical properties and exert traction forces that deform it. This mechanical interplay between cells and the ECM, many aspects of which remain incompletely understood, involves the coordination of processes acting at different spatial scales and is highly influenced by the mechanical properties of the cells, ECM and focal adhesion components. To gain a better understanding of these mechanical interactions, we have developed a multiscale agent-based model based on a mechanical description of forces that simultaneously integrates the mechanosensitive regulation of focal adhesions, cytoskeleton dynamics, and ECM deformation. We use our model to quantify cell-cell communication mediated by ECM deformation and to show how this process depends on the mechanical properties of cells, the ECM fibres and the topology of the ECM network. In particular, we analyse the influence of ECM stiffness and cell contraction activity in the transmission of mechanical cues between cells and how the distinct timescales associated with different processes influence cell-ECM interaction. Our model simulations predict increased ECM deformation for stronger cell contraction and a sweet spot of ECM stiffness for the transmission of mechanical cues along its fibres. We also show how the network topology affects the ability of stiffer ECMs to transmit deformation and how it can induce cell detachment from the ECM. Finally, we demonstrate that integrating processes across different spatial and temporal scales is crucial for understanding how mechanical communication influences cell behaviour.