Stiffness Decouples Cellular Mechanosensation

Main Text

The cell-cell and cell-extracellular matrix (ECM) “cross talk” is very critical in understanding the collective behavior of monolayer sheets (1), and a thorough illustration of this process represents one of the “holy grails” within the field. The novel and exciting model proposed by Vargas et al. (2) in this issue of the Biophysical Journal captures the dynamics involved in cell-ECM and cell-cell interactions. Consideration of the factors previously mentioned into the model presented by Vargas et al. is very powerful as this model has the ability to predict the tipping point for cell decoupling. An understanding of cell decoupling has the potential to unravel the enigma around the competition and struggle between cell-cell adhesion forces and cell-ECM adhesion forces. Furthermore, Vargas et al. provides a comprehensive model depicting the viscoelastic nature of the cell through the Kelvin-Voigt model while also taking into account the contact forces, rate of actin disassembly, and strength gradient of focal adhesion (FA) and adherence junction (AJ) fibers that are sensitive to fiber stiffness and fiber length. These factors are what ultimately allow for estimation of the “cutoff point” of ECM stiffness at which cell decoupling occurs. Vargas et al. meticulously unified a system of cell pair and ECM by modeling the lamellipodium, lamellum, and AJ and FA stress cables through the utilization of discrete element analysis. The concurrent simulation of FA forces, AJ forces, and cell dynamics for various ECM environments prove to be instrumental in providing deeper insights into the complex interactions between cell-cell adhesion forces and cell-substrate adhesion forces.

The model presented by Vargas et al. and subsequent explanations presented by Vargas et al. represent a significant potential to advance the field, and their computational analysis shed light on previously unexplained cellular biophysical mechanisms. The dimensionless “coupling factor” could be crucial in quantifying the cell-cell decoupling owing to environmental factors (ECM stiffness), for example. Furthermore, the physiological implications are extensive: from understanding disease progression to cell mechanics of cancer and other cell types (2). Another interesting aspect to look at is the simulation of the cell pair-ECM system in which cell-cell forces dominate cell-ECM forces severalfold. This could clarify phenomenon like “cell jamming” in which frictional forces increase over time, which could be simulated by the model (3,4). The model could also be useful for discerning the transition from fluid to solid-like behavior seen in cells owing to high cellular density and cell-cell frictional forces relative to cell-ECM tractions (5,6). The extension of this model to a system of cellular monolayer on the substrate could be very insightful in comprehending the collective dynamics at the tissue level. There are so many things to unriddle when it comes to the mechanobiology of cells, and the model presented by Vargas et al. represents significant progress toward achieving these goals.