Multiscale modelling shows how cell-ECM interactions impact ECM fibre alignment and cell detachment
Authors: Arellano-Tintó Juan , Stepanova Daria , Byrne Helen M. , Maini Philip K. , Alarcón Tomás 
Published: December 2024

AbstractThe 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.Author summaryThe cell surrounding is a dynamic fibrous network known as the extracellular matrix (ECM). It supports and influences cell behaviour, playing a key role in cell communication, growth, and migration. Cells sense the ECM’s mechanical properties and exert traction forces on it, leading to the deformation of matrix fibres and the transmission of mechanical stress. These changes are transmitted along the ECM fibres, influencing the behaviour of neighbouring cells. Different subcellular structures and extracellular matrix components interact at various spatial and temporal scales, making mathematical modelling a valuable tool for analysing these interactions. We have developed a multiscale force-based model that quantifies mechanical stress transmission, captures cell detachment, and explores the impact of mechanical properties of both cells and the ECM. Our analysis shows that stronger cell contraction increases extracellular matrix deformation and suggests a range of extracellular matrix stiffness for effective mechanical cell-cell communication. We also use our model to investigate how ECM network topology can induce cell detachment by modifying the ability of stiff ECMs to transmit deformation when subject to cell-induced traction forces. Our results show the importance of coupling the processes occurring at different scales to capture the overall behaviour.