Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions

The isotropic or anisotropic organisation of biological extracellular matrices has important consequences for tissue function. We study emergent anisotropy using fibroblasts that generate varying degrees of matrix alignment from uniform starting conditions. This reveals that the early migratory paths of fibroblasts are correlated with subsequent matrix organisation. Combined experimentation and adaptation of Vicsek modelling demonstrates that the reorientation of cells relative to each other upon collision, plays a role in generating matrix anisotropy. We term this behaviour cell collision guidance. The transcription factor TFAP2C regulates cell collision guidance, in part by controlling the expression of RND3. RND3 localises to cell-cell collision zones where it locally down-regulates actomyosin activity. Without this mechanism in place cell collision guidance fails leading to isotropic matrix generation. Cross-referencing alignment and TFAP2C gene expression signatures against existing datasets enables the identification and validation of several classes of pharmacological agents that disrupt matrix anisotropy.