Dual Mechanical Signal Integration Reveals Non Linear Cell Behavior

Abstract

Cell signaling is a complex, dynamic process, that requires precise coordination between internal signaling cascades and pathways and external environmental cues. One such external cue is mechanical stimulation which is known to influence a variety of cell responses including motility and proliferation. While mechanical stimulation may come in the form of tension, compression, or shear via a static or cyclic mode it may also occur separately or simultaneously reflecting the diversity of mechanical signals that cells may be required to integrate into cell behavior. For example, one cell type that experiences coupled mechanical influences are endothelial cells, which undergo three mechanical stresses: parallel shear flow, perpendicular radial stretch, and circumferential wall stress. Both normal and abnormal physiological processes result from the interplay between these forces. To probe how the cell integrates multiple mechanical signals single cells were exposed to uniaxial stretching, shear fluid flow and both modes of stimulation simultaneously to examine how the cell processes multiple inputs of mechanical stimulation as a function of cellular orientation. Cells exposed to single modes of mechanical stimulation were observed to align along the direction of stress, but intriguingly when combined, the responses were out of phase where the cells aligned between the direction of applied stresses with an orientation that was neither vertical or horizontal. This signal integration was observed to be not simply an additive approach, which has been investigated for physiological processes, but rather a non-linear combination between both modes of mechanical stimulation, which is interesting as this has implications in abnormal physiological implications. These results will help provide insight into the complexities of cell behaviour and have implications in a variety of fields including biophysics, mechanotransduction, and cell signaling.