Slow local movements of collagen fibers by fibroblasts drive the rapid global self-organization of collagen gels

A classic model for tissue morphogenesis is the formation of ligament-like straps between explants of fibroblasts placed in collagen gels. The patterns arise from mechanical forces exerted by cells on their substrates (Harris et al., 1981). However, where do such straps come from, and how are slow local movements of cells transduced into dramatic long-distance redistributions of collagen? We embedded primary mouse skin and human periodontal ligament fibroblasts in collagen gels and measured the time course of patterning by using a novel computer algorithm to calculate anisotropy, and by tracking glass beads dispersed in the gel. As fibroblasts began to spread into their immediate environments, a coordinated rearrangement of collagen commenced throughout the gel, producing a strap on a time scale of minutes. Killing of cells afterwards resulted in a partial relaxation of the matrix strain. Surprisingly, relatively small movements of collagen molecules on the tensile axis between two pulling explants induced a much larger concomitant compression of the gel perpendicular to the axis, organizing and aligning fibers into a strap. We propose that this amplification is due to the geometry of the collagen matrix, and that analogous amplified movements may drive morphological changes in other biological meshes, both outside and inside the cell.