Cell contact guidance via sensing anisotropy of network mechanical resistance

Significance Cell contact guidance in aligned fibers is, in many ways, a final frontier in directed cell migration. Despite its ubiquitous importance in normal/pathological processes, notably metastasis from solid tumors, and scaffold design for tissue engineering/regenerative medicine, the signal that induces contact guidance in an aligned fiber network has defied elucidation. We report definitive demonstration of a biophysical signal sensed by fibroblasts cultured within aligned fibrils: mechanical resistance anisotropy, the resistance resulting from viscous and elastic properties of fibril network to pseudopod protrusion/retraction and how it differs in different directions (anisotropy). This discovery is of fundamental importance to understanding contact guidance, providing a rationale, currently lacking, for future studies of the intracellular signal transduction/response pathways for physiologically relevant contact guidance.