Directional Cell Migration Guided by a Strain Gradient

Abstract

Strain gradients, a graded change in the percentage of the deformation across a continuous field by applying forces, widely exist in development and physiological activities. The directional movement of cells is essential for proper cell localization, and directional cell migration in responses to gradients of chemicals, rigidity, and density and topography of extracellular matrices have been well-established. However, it is unclear whether strain gradients imposed on cells are sufficient to drive directional cell migration. In this work, we develop a programmable uniaxial cell stretch device coupled with geometrical constraints to create controllable strain gradients on cells. We demonstrate that single rat embryonic fibroblasts respond to very small strain gradients. In a gradient level of [~]4% per mm, over 60% of the REFs prefer to migrate towards the lower strain side in both the static and the 0.1 Hz cyclic stretch conditions. We confirm that such responses to strain gradient are distinct from durotaxis or haptotaxis. Moreover, we discover that the directional migration of the cells is initiated by increased focal adhesion contact areas and higher rate of protrusion formation on the lower strain side of the cell. We further establish a 2D extended motor-clutch model to explain the molecular mechanism. Through our model, we find that the strain-introduced traction force determines integrin fibronectin pairs catch-release dynamics, which drives such directional migration. Together, our results establish strain gradient as a novel cue to regulate directional cell migration and may provide new insights into development and tissue repairs.