Mechanosensitivity of amoeboid cells crawling in 3D

Abstract

Efficient immune-responses require migrating leukocytes to be in the right place at the right time. When crawling through the body amoeboid leukocytes must traverse complex three-dimensional tissue-landscapes obstructed by extracellular matrix and other cells, raising the question how motile cells adapt to mechanical loads to overcome these obstacles. Here we reveal the spatio-temporal configuration of cortical actin-networks rendering amoeboid cells mechanosensitive in three-dimensions, independent of adhesive interactions with the microenvironment. In response to compression, Wiskott-Aldrich syndrom protein (WASp) assembles into dot-like structures acting as nucleation sites for actin spikes that in turn push against the external load. High precision targeting of WASp to objects as delicate as collagen fibers allows the cell to locally and instantaneously deform its viscoelastic surrounding in order to generate space for forward locomotion. Such pushing forces are essential for fast and directed leukocyte migration in fibrous and cell-packed tissues such as skin and lymph nodes.

WASP integrates substrate topology and cell polarity to guide neutrophil migration

“…7, A and B ). This behavior was also recently observed for WASP in dendritic cells ( Gaertner et al, 2021 Preprint ). Unlike focal adhesions that form on both the ridges and the grooves of these patterns ( Ray et al, 2017 ), WASP localized specifically to the positive (inward) curvature-inducing ridges.…”

“…Indeed, invadopodia concentrate their actin polymerization and matrix degradation at collagen fibers that indent the cell and impede cell movement ( Ferrari et al, 2019 ), and podosomes only become exvaginations upon actomyosin contraction ( Labernadie et al, 2010 ) and may be initiated through other membrane deformations. In dendritic cells, WASP stimulates focal actin-based protrusions in response to local compression ( Gaertner et al, 2021 Preprint ). A response to membrane invaginations may represent a shared feature of these cellular structures despite the differences in their ultimate morphology.…”

Macrophages sense ECM mechanics and growth factor availability through cytoskeletal remodeling to regulate their tissue repair program

“…However, one fundamental distinction is that, while mesenchymal migration depends on binding to the ECM and pulling to achieve locomotion, amoeboid migration does not require adhesion and instead depends instead on actin filaments pushing outward at the cell membrane against compressive forces. [39][40][41][72][73][74][75] Rather than sensing mechanical tension, therefore, macrophages are likely to sense mechanical compression as they migrate within the tissue. In other words, macrophage mechanosensing may work by pushing, rather than pulling.…”