Microenvironmental control of cell migration: Myosin IIA is required for efficient migration in fibrillar environments through control of cell adhesion dynamics

Abstract

Recent evidence suggests that organization of the extracellular matrix (ECM) into aligned fibrils or fibril-like ECM topographies promotes rapid migration in fibroblasts. However, the mechanisms of cell migration altered by these changes in microenvironmental topography remain unknown. Here, using 1D fibrillar migration as a model system for oriented fibrillar 3D matrices, we find that fibroblast leading edge dynamics are enhanced by 1D fibrillar micropatterns and demonstrate a dependence on the spatial positioning of cell adhesions. Although 1D, 2D, and 3D matrix adhesions have similar assembly kinetics, both 1D and 3D adhesions are stabilized for prolonged periods, while both paxillin and vinculin show slower turnover rates in 1D adhesions. Moreover, actin in 1D adhesions undergoes slower retrograde flow than the actin present in 2D lamellipodia. These data suggest an increase in mechanical coupling between adhesions and protrusive machinery. Experimental reduction of contractility resulted in loss of 1D adhesion structure and stability, with scattered small and unstable adhesions and an uncoupling of adhesion protein-integrin stability. Genetic ablation of myosin IIA or IIB isoforms revealed that myosin IIA is required for efficient migration in restricted environments as well as adhesion maturation, while myosin IIB helps to stabilize adhesions beneath the cell body. These data suggest that restricted cell environments such as 1D patterns require cellular contraction via myosin IIA to enhance adhesion stability and coupling to integrins behind the leading edge. This increase in mechanical coupling allows for greater leading edge protrusion and rapid cell migration.