Loss of vimentin intermediate filaments increases motility and nuclear damage in confining spaces

Cell migration is important to many biological processes, such as embryogenesis, wound healing, and cancer metastasis. The proper migration of cells is regulated by the mechanical properties of the cytoskeleton. The cytoskeleton is comprised of three main polymers, F-actin, microtubules, and intermediate filaments. When cells transition from stationary to migratory states, they often upregulate the intermediate filament vimentin. The viscoelasticity of vimentin networks in shear deformation has been documented, but its role in motility remains largely mysterious. Here, we used mouse embryo fibroblasts derived from wild-type and vimentin-null mice and examined their migration in microfluidic constrictions. We find that loss of vimentin increases 3D motility, unlike on rigid 2D substrates. Migrating through small constrictions leads to stress-induced nuclear damage in the form of blebs, nuclear envelope rupture, and double-stranded DNA breaks. These nuclear damage markers increase in the absence of a filamentous vimentin network. Our findings indicate that vimentin hinders 3D motility by providing mechanical resistance against large strains and thereby protects the structural integrity of the cell.