Intermediate filaments control collective migration by restricting traction forces and sustaining cell–cell contacts

Abstract

Mesenchymal cell migration relies on the coordinated regulation of the actin and microtubule networks that participate in polarized cell protrusion, adhesion, and contraction. During collective migration, most of the traction forces are generated by the acto-myosin network linked to focal adhesions at the front of leader cells, which transmit these pulling forces to the followers. Here, using an in vitro wound healing assay to induce polarization and collective directed migration of primary astrocytes, we show that the intermediate filament (IF) network composed of vimentin, glial fibrillary acidic protein, and nestin contributes to directed collective movement by controlling the distribution of forces in the migrating cell monolayer. Together with the cytoskeletal linker plectin, these IFs control the organization and dynamics of the acto-myosin network, promoting the actin-driven treadmilling of adherens junctions, thereby facilitating the polarization of leader cells. Independently of their effect on adherens junctions, IFs influence the dynamics and localization of focal adhesions and limit their mechanical coupling to the acto-myosin network. We thus conclude that IFs promote collective directed migration in astrocytes by restricting the generation of traction forces to the front of leader cells, preventing aberrant tractions in the followers, and by contributing to the maintenance of lateral cell-cell interactions.

Regulation of keratin network dynamics by the mechanical properties of the environment in migrating cells

“…The isotype-specific effects of overexpressing and downregulating specific keratins still remains to be untangled to understand the sometimes opposing results in different contexts (recent review 8 ; for effects in keratinocytes see also 38,39 ). Another recent study by De Pascalis et al 40 We conclude that keratin flow patterns very closely reflect migratory behaviour and are controlled by actin dynamics. Increased keratin flow correlates with increased migration in multiple paradigms.…”

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

“…Despite several recent studies addressing the interplay between vimentin IFs and FAs (e.g., [10,46,48,64,65], for review see [66]), the underlying mechanisms remain somewhat enigmatic. Specifically, Terriac et al revealed, using stimulated emission depletion (STED) microscopy, that vimentin is found in most, but not all, FAs, and that vimentin IFs are localized at large FAs in transformed fibroblasts [58].…”

“…Interestingly, the cells were more effective at migrating when they were more densely plated on the membrane, although they migrated through it individually [12]. The role of vimentin in collective migration was also investigated in astrocytes where it appeared that vimentin IFs regulated the distribution of traction forces and the maintenance of cell-cell interactions, thus contributing to successful collective migration [65]. In collective migration induced by interstitial fluid pressure, vimentin was among the upregulated genes [96].…”

Hemidesmosomes modulate force generation via focal adhesions

“…They sense and respond to both intrinsic and extracellular forces (Iskratsch et al, 2014;Oria et al, 2017;Schwartz, 2010) and play an important role in many cellular processes that are driven by mechanotransduction, including cell adhesion, polarized migration, and differentiation (Jansen et al, 2017). In contrast to the FA-anchored actomyosin cytoskeleton, the HD-associated IF system enables cells to withstand mechanical stress and tension (Sanghvi-Shah and Weber, 2017;De Pascalis et al, 2018;Goldmann, 2018). However, it is unclear whether HD-associated IFs can also reduce cellular tension generated by the actomyosin cytoskeleton.…”