Membrane Tension Can Enhance Adaptation to Maintain Polarity of Migrating Cells

Abstract

Migratory cells are known to adapt to environments that contain wide-ranging levels of chemoattractant. While biochemical models of adaptation have been previously proposed, here we discuss a different mechanism based on mechanosensing, where the interaction between biochemical signaling and cell tension facilitates adaptation. We describe and analyze a model of mechanochemical-based adaptation coupling a mechanics-based physical model of cell tension coupled with the wave-pinning reaction-diffusion model for Rac activity. Mathematical analysis of this model, simulations of a simplified 1D cell geometry, and 2D finite element simulations of deforming cells reveal that as a cell protrudes under the influence of high stimulation levels, tension mediated inhibition of GTPase signaling causes the cell to polarize even when initially over-stimulated. Specifically, tension mediated inhibition of GT-Pase activation, which has been experimentally observed in recent years, facilitates this adaptation by countering the high levels of environmental stimulation. These results demonstrate how tension related mechanosensing may provide an alternative (and potentially complementary) mechanism for cell adaptation. Statement of SignificanceMigratory cells such as human neutrophils encounter environments that contain wide-ranging levels of chemoattractant. In order to move, these cells must maintain an organized front-rear signaling polarity despite this wide variation in environmental stimuli. Past research has demonstrated a number of biochemical based mechanisms by which cells adapt to variable signal levels. Here we demonstrate that the interplay between Rho GTPase signaling and tension mediated feedbacks may provide an alternative mechanochemical mechanism for adaptation to high levels of signaling.

Three-dimensional stochastic simulation of chemoattractant-mediated excitability in cells

“…There is also inhibition that contributes to the polarization of cells and comes from the cytoskeleton [ 51 ] which we did not model here. We and others [ 93 – 95 ] have suggested that this may be related to mechanical properties of the cell. However, while both these processes provide inhibition, they are not the I that we propose in this paper, which is specific to the LEGI mechanism.…”

“…In particular, wave pinning could be caused by the localization of signaling molecules in cell structures that represent significantly different surface-to-volume characteristics, like filopodia, dendritic spines, and primary cillia [ 102 ]. The resultant changes in cortical tension could also affect polarization in cells [ 37 , 94 , 95 ]. Change in the membrane curvature also recruit curvature-sensing proteins such as Bar-domain proteins which are known to interact with the signaling network at various levels [ 103 , 104 ].…”

Pannexin Channel Regulation of Cell Migration: Focus on Immune Cells

“…In addition, PANX1 channels are somehow mechanosensitive, although in a lesser extent in comparison to other channels such as Piezo1 and Piezo2 ( 145 ). Still PANX1 could quickly react to changes in the membrane tension ( 96 , 100 , 146 ), providing a fast feedback mechanism in which the opening of the channel can be controlled by the mechanical cues of the microenvironment that surrounds the migrating cell. This could be sustained in time by the activation of enzymes that directly modify the opening of the channel, such as Ca 2+ -sensitive CaMKII ( 72 ), or by a positive feedback with P2 receptors ( 147 , 148 ) ( Figures 2 , 3 ).…”

Cellular tango: How extracellular matrix adhesion choreographs Rac-Rho signaling and cell movement

“…This suggests that cell biophysics is an important factor in cell migratory behaviour that should be more closely examined in the context of intracellular signaling. See [34] for an example of this type.…”

“…Various mathematical models have considered GTPase dynamics within a cell but most of these studies only focused on cell polarization, such as [26,27,28,29,30,31,32,33,34,35] and others. The role of cell-ECM adhesion has been mathematically modelled and studied in detail in the context of cell spreading and directional migration (see e.g.…”