Frequency-Dependent Focal Adhesion Instability and Cell Reorientation Under Cyclic Substrate Stretching

Abstract

The adhesion-based cell mechanosensitivity plays central roles in many physiological and pathological processes. Recently, quantitative understanding of cell responses to external force has been intensively pursued. However, the frequency dependent cell responses to the substrate stretching have not yet been fully understood. Here we developed a multiscale modeling framework for studying cell reorientation behaviors under substrate stretching, in which the mechano-chemical coupling at molecular, subcellular, and cellular scales was considered. The effect of matrix stiffness was also considered in a FEM based mechano-chemical coupling simulation. We showed that the collapsing time of focal adhesion decreases with the increasing of the loading frequency, however, the cell reorientation time exhibits a biphasic frequency-dependent behavior. Our results suggested that this biphasic behavior might be caused by the competition between the frequency-dependent collapsing of focal adhesions and the less frequency-dependent formation of stress fibers aligning away from the loading direction. At the low loading frequency, the collapsing of focal adhesion dominates the reorientation process, however, at the high loading frequency the polymerization of stress fiber dominates the reorientation. Moreover, we showed that the compliance of matrix may help accelerate the cell reorientation because focal adhesion is prone to be instable on soft matrix.