Troaca-Luchici, LA; (2017) The Role of Forces During Contact Inhibition of Locomotion. Doctoral thesis , UCL (University College London).

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Abstract

Contact Inhibition of Locomotion (CIL), a process where migrating cells repel upon collision, was first observed in cultured cells more than 60 years ago. Previous work investigating Drosophila hemocyte collisions in vivo revealed that precise CIL interactions are required for hemocytes to acquire their developmental patterning. Kinematics analysis of the exact velocity and acceleration changes surrounding the contact inhibition process revealed that rapid and synchronous kinematic changes take place during collisions. To understand the cause of such intriguing CIL kinematics I examined the actin network dynamics surrounding collisions. Pseudo-speckle microscopy tracking the actin retrograde flow dynamics during collisions revealed that the actin flow un¬dergoes synchronous temporal and spatial reorganization across the entire lamella of both colliding partners. Also, a region of low retrograde flow develops perpen¬dicular to the leading edge spanning colliding cells. Upon repulsion, retrograde flow simultaneously spikes in both lamellae. Further experimental investigations revealed that as hemocytes collide, an inter-cellular adhesion develops at the site of cell-cell contact which leads to the formation of an actin stress-fibre like structure transiently coupling the cells through an actin clutch-like mechanism analogous to the integrin clutch encountered in migrating cells. I subsequently modelled the cytoskeletal stresses in freely moving and colliding cells using a linear viscoelastic model. Upon collision, lamellar stress redistributes from the cell body to the leading edge along the region of low retrograde flow. Direct laser abscission of the actin stress-fibre like structure spanning colliding cells confirmed that lamellar tension is increasing during CIL and showed that the release of this excess tension is sufficient to cause cells to migrate away from the collision. It is this haptic feedback mechanism, and the subsequent release of lamellar tension, that allows CIL to act as a productive migratory cue for the hemocyte developmental patterning.

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