Microbuckling of fibrin provides a mechanism for cell mechanosensing

Abstract

Biological cells sense and respond to mechanical forces, but how such a mechanosensing process takes place in a nonlinear inhomogeneous fibrous matrix remains unknown. We show that cells in a fibrous matrix induce deformation fields that propagate over a longer range than predicted by linear elasticity. Synthetic, linear elastic hydrogels used in many mechanotransduction studies fail to capture this effect. We develop a nonlinear microstructural finite-element model for a fibre network to simulate localized deformations induced by cells. The model captures measured cell-induced matrix displacements from experiments and identifies an important mechanism for long-range cell mechanosensing: loss of compression stiffness owing to microbuckling of individual fibres. We show evidence that cells sense each other through the formation of localized intercellular bands of tensile deformations caused by this mechanism.

Fiber Network Models Predict Enhanced Cell Mechanosensing on Fibrous Gels

“…The results from this study support the growing body of experimental and theoretical work that indicates that the fibrous nature of biological gels is responsible for enhanced long-distance cell mechanosensing compared to nonfibrous gels [14][15][16][17]30,[46][47][48]. Several of these theoretical studies have found that the mechanosensing length scale of a cell increases when fibers are accounted for in the model [14,30,46,48].…”

“…If the surrounding material was represented instead by a homogeneous nonlinear strain-hardening material, then the stresses rapidly decayed a short distance away from the cells and no mechanical communication occurred between the two cells. Another key property of the networks that facilitates fiber alignment and the transmission of long-range mechanical signals is the low compressive resistance of the fibers (relative to the tensile stiffness), which Notbohm et al also reported and referred to as microbuckling [30]. In this context, microbuckling does not refer to a mechanism of failure, but instead means that less energy is needed for fibers in the network to compress in order to accommodate the realignment of other network fibers in tension.…”

“…Several of these theoretical studies have found that the mechanosensing length scale of a cell increases when fibers are accounted for in the model [14,30,46,48]. For example, Ma et al developed an image-based 2D FE model of two cells separated by a distance of $100 lm and surrounded by a network of linear elastic collagen fibers embedded in a soft nonfibrous material with mechanical properties selected from the literature [46].…”

“…As a result, continuum models may underestimate longrange mechanical sensing observed for cells on fibrous substrates where sensing distances up to several hundred microns have been reported [15,27,28]. Recently, several models that incorporate fiber networks have been proposed [14,[29][30][31][32]. Aghvami et al used a multiscale FE model to demonstrate that long-range force transmission from other cell clusters and from the gel boundaries controls fiber remodeling in a cell-compacted collagen gel [29].…”

“…Aghvami et al used a multiscale FE model to demonstrate that long-range force transmission from other cell clusters and from the gel boundaries controls fiber remodeling in a cell-compacted collagen gel [29]. Notbohm et al developed a nonlinear FE model for a fiber network representing fibrin gels and showed that cells in a fibrous matrix induce deformations that propagate longer distances than predicted by linear elasticity [30]. Abhilash et al presented an FE model for 2D discrete fiber networks created with linear elastic fibers and also captured cell-mediated collagen alignment, deformations, and long-range force transmission [31].…”