Curvotaxis directs cell migration through cell-scale curvature landscapes

Abstract

Cells have evolved multiple mechanisms to apprehend and adapt finely to their environment. Here we report a new cellular ability, which we term “curvotaxis” that enables the cells to respond to cell-scale curvature variations, a ubiquitous trait of cellular biotopes. We develop ultra-smooth sinusoidal surfaces presenting modulations of curvature in all directions, and monitor cell behavior on these topographic landscapes. We show that adherent cells avoid convex regions during their migration and position themselves in concave valleys. Live imaging combined with functional analysis shows that curvotaxis relies on a dynamic interplay between the nucleus and the cytoskeleton—the nucleus acting as a mechanical sensor that leads the migrating cell toward concave curvatures. Further analyses show that substratum curvature affects focal adhesions organization and dynamics, nuclear shape, and gene expression. Altogether, this work identifies curvotaxis as a new cellular guiding mechanism and promotes cell-scale curvature as an essential physical cue.

Topotaxis of active Brownian particles

“…In vivo, cells crawl through topographically intricate environments, such as the extracellular matrix, blood and lymphatic vessels, other cells, etc., that can significantly influence migration strategies [6][7][8][9]. For instance, it has been shown that local anisotropy in the underlying substrate, in the form of adhesive ratchets [10][11][12] or three-dimensional structures on the subcellular scale [10,13,14], can lead to directed motion even in the absence of chemical stimuli.…”

Chemotaxis and topotaxis add vectorially for amoeboid cell migration

“…The physical structure of the micro-environment around the cell, the 3D-topography, can act as a stimulus modulating cell direction and speed during migration 6 . In vitro topographical structures are typically made up out of channels [12][13][14][15] , ratchets [16][17][18] , grooves [19][20][21] , pillars [22][23][24] , curves 25 , or areas with increased alignment of extracellular matrix fibers 14,[26][27][28] . These topotaxis assays rely on topographical asymmetries, and exploit differences in slope, confinement or alignment to influence cell migration.…”

Laser‐Assisted Strain Engineering of Thin Elastomer Films to Form Variable Wavy Substrates for Cell Culture

“…Nevertheless, mimicking the physiological curvatures that characterize the in vivo environment is crucial to unravel biological and mechanical mechanisms modulated by geometrical confinement. In particular, recent efforts have been done to investigate the adaptation of cells and of nuclei to external mechanical properties, in the reciprocal regulation of their shape and functions (e.g., by anisotropic compressive forces or homogeneous curvatures). These studies support the more and more emergence of a direct mechanical continuity between the cytoskeleton and the nucleoskeleton, which has great significance for its intrinsically participation in cell differentiation and fate, gene expression, mechanical response to force, and pathogenic mutations …”

“…Recently, bigger concave or convex structures have also shown to guide cell orientation and migration . However, the use of these curved substrates is still rare in biological studies.…”