Vimentin inside and outside the cell: from cell spreading to nuclear mechanics to COVID-19

Cells are constantly subjected to both external forces encountered from the extracellular environment and internal stresses generated by the cell necessary to migrate and undergo healthy cellular function. Central to the ability of cells to both generate and mediate forces is the cell cytoskeleton, which forms the muscles and bones for cells. There are three main components of the cell cytoskeleton: microtubules, actin, and intermediate filaments. The role of actin and microtubules in cell function, particularly force generation and mediation have been well studied; however, the role of intermediate filaments is less understood. Intermediate filaments represent a broad and diverse family of proteins, where vimentin is the dominant cytoplasmic intermediate filament associated with mesenchymal cells. In this work, we discuss vimentin and the role it plays in three different contexts. First, we present findings that show the role vimentin plays in mechanosensing on substrates with viscous dissipation, demonstrating that vimentin should be considered in models for cellular mechanosensing and spreading on viscoelastic substrates, like tissue. Second, we look at extracellular vimentin, vimentin fragments found on the outer edge of the cell membrane of both healthy and ill tissue and cells, and the role it plays as a cofactor for infection with SARS-CoV-2 by pseudovirus particles. Our results indicate that vimentin may be a promising candidate for therapeutic treatments for SARS-CoV-2 through targeting extracellular vimentin with anti-vimentin antibodies, leading to reduced infection. Finally, we systematically study the role of vimentin and nesprin-3, a protein connecting intermediate filaments to the nuclear envelope, with geometric confinement using micropatterning. This work shows vimentin, mechanically linked to the nuclear envelope through nesprin-3, enhances nuclear deformation on high aspect ratio patterns. This suggests that vimentin has a role in transmitting forces to the nucleus and should be considered in a mechanical model of the cell. The work contained in this document highlights recent advancements in the field of vimentin intermediate filaments, and provides evidence for the importance of considering vimentin, and more broadly intermediate filaments, in cell mechanics and health.