Directional Cell Migration Guided by a Strain Gradient

Abstract

ABSTRACTStrain gradients, the percentage of the deformation changed across a continuous field by applying forces, have been observed in developing tissues due to the inherent heterogeneity of the mechanical properties. The directional movement of cells are essential for proper cell localization, and it is well-established that cells establish directional migration in responses to gradients of chemicals, rigidity, density of extracellular matrices, and topography of substrates. However, it is unclear whether strain gradients imposed on cells due to tissue growth 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 (REFs) respond to very small strain gradients. In a gradient level of 4% per mm, 60%-70% 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 is distinct from durotaxis or haptotaxis. Moreover, by using the YFP-Paxillin reporter, we discover that the directional migration of the cells is initiated by increasing focal adhesion contact areas and higher rate of protrusion formation in the lower strain side of the cell. Together, in this work we establish strain gradient as a novel cue to regulate directional cell migration and may provide new insights in development and tissue repairs.