Cell Migration in Mechanically Resistive Environment

Abstract

The mechanical environment of a cell influences its migration. It has been observed that certain cell types such as Dictyostelium and cancer cells tend to migrate by forming blebs rather than pseudopodia in mechanically resistive environment. However, very little is known about the mechanisms governing this transition between different modes of migration. In this work, we disentangle the contributions of two key mechanical factors that might trigger this switch, the environment's stiffness (the extent of local deformation of extra-cellular matrix) and its state of stress (amount of pre-existing tension or compression).A custom built device, “cell squasher”, is used to apply dynamically controlled and uniform force on cells chemotaxing under an agaorse layer. Our results show that switch to bleb mode of migration can be triggered by an increase in either the external load imposed by the device or gel stiffness. This transition is also associated with a decrease in cell speed. Increasing the load even further triggers the rounding up of the cells and dramatically slows down the retraction of blebs; migration ceased in most of the cases. These results show quantitatively that a lower threshold of load is required for switching as gel stiffness increases which implies a collaborative effect of both the physical parameters. Surprisingly, the cells also undergo a significant reduction in their volume within few minutes of the imposition of the load. We also show that cells become highly contractile under load and myosin recruitment to cortex takes place leading to some loss of polarity. The cells also migrate in less adhesive manner under load condition. The involvement of Pip3, Rac, Ras and SCAR signaling in protrusion switching is also seen. This work is of significant importance in quantitatively understanding the effect of physical changes in migration of cells.