Branched and Linear F-actin Networks Control Directional Migration Switching Behavior on Aligned Collagen Fibrils

Directed cell migration is essential in biological processes like embryonic development, wound healing and cancer metastasis and is driven by a variety of directional cues, including aligned fibrils in the extracellular matrix (ECM), a phenomenon known as contact guidance. How different cells respond to aligned fibrils and how external factors like ECM stiffness and internal regulators like formins and Arp2/3 control contact guidance across different type of cells is unknown. In this study, a unique system to assemble aligned collagen fibrils on mica and to transfer them onto substrates with specified stiffness is used to probe how external factors and internal regulators affect contact guidance. This system reveals distinct contact guidance behaviors: mesenchymal cells exhibit high-fidelity contact guidance, amoeboid cells ignore cues and epithelial cells use a mixture of both parallel and perpendicular migration on aligned collagen fibrils. Formins and Arp2/3 exert reciprocal control over contact guidance across a variety of cell types, where formins mediators of linear F-actin structures enhance contact guidance and Arp2/3 a mediator of branched F-actin structures diminishes contact guidance. This controlled materials system reveals important external and internal mechanisms of how contact guidance directs cell migration across a variety of different cell types.