Search

In vivo, eukaryotic cells are embedded in a matrix environment, where they grow and develop. Generally, this extracellular matrix (ECM) is an anisotropic fibrous structure, through which macromolecules and biochemical signaling molecules at the nanometer scale diffuse. The ECM is continuously remodeled by cells, via mechanical interactions, which lead to a potential link between biomechanical and biochemical cell-cell interactions. Here, we study how cell-induced forces applied on the ECM impacts the biochemical transport of molecules between distant cells. Experimentally, we observe that cells remodel the ECM by increasing fiber alignment and density of the matrix between them over time. Using random walk simulations on a 3D lattice, we implement elongated fixed obstacles that mimic the fibrous ECM structure. We measure both diffusion of a tracer molecule and the mean first-passage time a molecule secreted from one cell takes to reach another cell. Our model predicts that cell-induced remodeling can lead to a dramatic speedup in the transport of molecules between cells. Fiber alignment and densification cause reduction of the transport dimensionality from a 3D to a much more rapid 1D process. Thus, we suggest a novel mechanism of mechano-biochemical feedback in the regulation of long-range cell-cell communication.

Biological cells embedded in fibrous matrices have been observed to form inter-cellular bands of dense and aligned fibers, through which they mechanically interact over long distances. Such matrix-mediated cellular interactions have been shown to regulate a variety of biological processes. The current study was aimed at exploring the effects of elastic nonlinearity of the fibers contained in the extracellular matrix (ECM) on the transmission of mechanical loads between contracting cells. Based on our biological experiments, we developed a finite-element model of two contracting cells embedded within a fibrous network. The individual fibers were modeled as showing either linear elasticity, compression-microbuckling, tension-stiffening or both of the latter. Compression-buckling resulted in smaller loads occurring in the ECM, but these were more directed toward the neighboring cell. The latter decreased with increasing cell-to-cell distance; when cells were >15 cell-diameters apart, no such inter-cellular interaction was observed. Tension-stiffening further contributed to directing the loads toward the neighboring cell, though to a smaller extent. The contraction of two neighboring cells resulted in mutual attraction forces, which were considerably increased by tension-stiffening, and decayed with increasing cell-to-cell distances. Nonlinear elasticity contributed also to the onset of force polarity on the cell boundary. The density and alignment of the fibers within the inter-cellular band were considerably greater when fibers buckled under compression, with tension-stiffening further contributing to this structural remodeling. Our model demonstrates the contribution of nonlinear elasticity of biological gels to directionality and efficiency of mechanical-signal transfer between distant cells.