Fibers in the Extracellular Matrix Enable Long-Range Stress Transmission between Cells

Abstract

Cells can sense, signal, and organize via mechanical forces. The ability of cells to mechanically sense and respond to the presence of other cells over relatively long distances (e.g., ∼100 μm, or ∼10 cell-diameters) across extracellular matrix (ECM) has been attributed to the strain-hardening behavior of the ECM. In this study, we explore an alternative hypothesis: the fibrous nature of the ECM makes long-range stress transmission possible and provides an important mechanism for long-range cell-cell mechanical signaling. To test this hypothesis, confocal reflectance microscopy was used to develop image-based finite-element models of stress transmission within fibroblast-seeded collagen gels. Models that account for the gel's fibrous nature were compared with homogenous linear-elastic and strain-hardening models to investigate the mechanisms of stress propagation. Experimentally, cells were observed to compact the collagen gel and align collagen fibers between neighboring cells within 24 h. Finite-element analysis revealed that stresses generated by a centripetally contracting cell boundary are concentrated in the relatively stiff ECM fibers and are propagated farther in a fibrous matrix as compared to homogeneous linear elastic or strain-hardening materials. These results support the hypothesis that ECM fibers, especially aligned ones, play an important role in long-range stress transmission.

Inelastic behaviour of collagen networks in cell–matrix interactions and mechanosensation

“…This notion is also supported by the smaller bead displacements at each point along the cell extensions in thin attached gels compared with floating gels. Remote, in-depth mechanosensing is thought to influence the morphology and function of cells plated on thin attached matrices [41,42], but this notion needs to consider the effect of rigid foundations on the mechanics of collagen gels. Unlike elastic substrates that preserve cell-induced tension in the network, native collagen matrices also exhibit inelastic behaviour, which can release cell-generated tension.…”

Heterogeneous force network in 3D cellularized collagen networks

“…Specifically, tension exerted by the cells can align the fibers in the network leading to long range force transmission [14,16,17]. Fiber mediated stresses can trigger mechano-sensitive pathways of distant cells affecting behaviors such as force * Electronic address: yang.jiao.2@asu.edu generation [18,19] and cell-ECM adhesions [20] and leading to diverse collective behaviors [21].…”

“…In addition, the transport properties (e.g., macromolecule diffusivity) [32,[37][38][39][40][41][42][43][44][45][46] and mechanical properties (e.g., elastic moduli, bulk rheology, stress distribution, etc.) [14,16,18,35,[47][48][49][50][51][52][53] of biopolymer network, which are respectively crucial to the chemical and mechanical signalling between the cells, strongly depend on the network microstructure.…”

“…Specifically, high-resolution 2D confocal images of cellularized ECM are thresholded to generate a three-phase heterogeneous system including a cell phase, a fiber phase and an interstitial fluid phase [16]. Finite element analysis is then employed to obtain stress distribution in the ECM.…”

“…Recently, continuum models of cellularized collagen network have been developed to investigate the fibermediated mechanical coupling between the cells [16,54]. Specifically, high-resolution 2D confocal images of cellularized ECM are thresholded to generate a three-phase heterogeneous system including a cell phase, a fiber phase and an interstitial fluid phase [16].…”