Dataset Information

Cell Mechanics at the Rear Act to Steer the Direction of Cell Migration.

ABSTRACT: Motile cells navigate complex environments by changing their direction of travel, generating left-right asymmetries in their mechanical subsystems to physically turn. Currently, little is known about how external directional cues are propagated along the length scale of the whole cell and integrated with its force-generating apparatus to steer migration mechanically. We examine the mechanics of spontaneous cell turning in fish epidermal keratocytes and find that the mechanical asymmetries responsible for turning behavior predominate at the rear of the cell, where there is asymmetric centripetal actin flow. Using experimental perturbations, we identify two linked feedback loops connecting myosin II contractility, adhesion strength and actin network flow in turning cells that are sufficient to explain the observed cell shapes and trajectories. Notably, asymmetries in actin polymerization at the cell leading edge play only a minor role in the mechanics of cell turning-that is, cells steer from the rear.

SUBMITTER: Allen GM

PROVIDER: S-EPMC7530145 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cell Mechanics at the Rear Act to Steer the Direction of Cell Migration.

Allen Greg M GM Lee Kun Chun KC Barnhart Erin L EL Tsuchida Mark A MA Wilson Cyrus A CA Gutierrez Edgar E Groisman Alexander A Theriot Julie A JA Mogilner Alex A

Cell systems 20200910 3

Motile cells navigate complex environments by changing their direction of travel, generating left-right asymmetries in their mechanical subsystems to physically turn. Currently, little is known about how external directional cues are propagated along the length scale of the whole cell and integrated with its force-generating apparatus to steer migration mechanically. We examine the mechanics of spontaneous cell turning in fish epidermal keratocytes and find that the mechanical asymmetries respon ...[more]

PMID: 32916096

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Project description:Cell migration in 3D microenvironments is a complex process which depends on the coordinated activity of leading edge protrusive force and rear retraction in a push-pull mechanism. While the potentiation of protrusions has been widely studied, the precise signalling and mechanical events that lead to retraction of the cell rear are much less well understood, particularly in physiological 3D extra-cellular matrix (ECM). We previously discovered that rear retraction in fast moving cells is a highly dynamic process involving the precise spatiotemporal interplay of mechanosensing by caveolae and signalling through RhoA. To further interrogate the dynamics of rear retraction, we have adopted three distinct mathematical modelling approaches here based on (i) Boolean logic, (ii) deterministic kinetic ordinary differential equations (ODEs) and (iii) stochastic simulations. The aims of this multi-faceted approach are twofold: firstly to derive new biological insight into cell rear dynamics via generation of testable hypotheses and predictions; and secondly to compare and contrast the distinct modelling approaches when used to describe the same, relatively under-studied system. Overall, our modelling approaches complement each other, suggesting that such a multi-faceted approach is more informative than methods based on a single modelling technique to interrogate biological systems. Whilst Boolean logic was not able to fully recapitulate the complexity of rear retraction signalling, an ODE model could make plausible population level predictions. Stochastic simulations added a further level of complexity by accurately mimicking previous experimental findings and acting as a single cell simulator. Our approach highlighted the unanticipated role for CDK1 in rear retraction, a prediction we confirmed experimentally. Moreover, our models led to a novel prediction regarding the potential existence of a 'set point' in local stiffness gradients that promotes polarisation and rapid rear retraction.

Dataset Information

Cell Mechanics at the Rear Act to Steer the Direction of Cell Migration.

Publications

Cell Mechanics at the Rear Act to Steer the Direction of Cell Migration.

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