Mechanics and Mechanisms of 3D Mesenchymal Cell Migration

Abstract

Cell migration has classically been characterized on two-dimensional (2D) surfaces as a series of distinct spatiotemporal steps. However, it remains unclear whether cells in a three-dimensional (3D) microenvironment use cell migration cycles or other mechanisms for efficient migration. Here, we describe a unique contractile mechanism employed by fibroblasts and mesenchymal cancer cells (HT-1080s) to migrate in 3D collagen gels. During 3D cell spreading, fibroblasts strongly deform the matrix. They protrude, polarize, and initiate migration in the direction of highest ECM deformation (prestrain). This prestrain is maintained through a novel uniaxial cellular contraction behind the leading edge prior to protrusion that coordinates a distinct 3D migration cycle that varies between cell types. We have found that myosin IIA is required for 1) polarizing force during spreading, 2) generating local uniaxial contraction, and 3) maintaining the matrix prestrain for efficient directional cell migration. Local matrix severing disrupts the matrix prestrain and migration, suggesting force transmission precedes migration. We find that epithelial cancer cells (MDA-MB-231) rarely demonstrate a sustained prestrain or uniaxial contraction seen in mesenchymal cells. We propose that mesenchymal cells can sense ECM stiffness in 3D and generate their own matrix prestrain using myosin IIA to migrate efficiently using polarized periodic uniaxial contractions for maintaining a unique 3D migration cycle.