Nonlinear Elasticity of the ECM Fibers Facilitates Efficient Intercellular Communication.

Biological cells embedded in fibrous matrices have been observed to form intercellular bands of dense and aligned fibers through which they mechanically interact over long distances. Such matrix-mediated cellular interactions have been shown to regulate various biological processes. This study aimed to explore 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 linear elasticity, compression microbuckling, tension stiffening, or both of the latter two. Fiber compression buckling resulted in smaller loads in the ECM, which were primarily directed toward the neighboring cell. These loads decreased with increasing cell-to-cell distance; when cells were >9 cell diameters apart, no such intercellular 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 boundaries, manifested by larger contractile forces pointing toward the neighboring cell. The density and alignment of the fibers within the intercellular band were greater when fibers buckled under compression, with tension stiffening further contributing to this structural remodeling. Although previous studies have established the role of the ECM nonlinear mechanical behavior in increasing the range of force transmission, our model demonstrates the contribution of nonlinear elasticity of biological gels to directional and efficient mechanical signal transfer between distant cells, and rehighlights the importance of using fibrous gels in experimental settings for facilitating intercellular communication. VIDEO ABSTRACT.