Formins and Arp2/3 Reciprocally Regulate Contact Guidance on Aligned Collagen Fibrils

Directed cell migration is essential in many biological processes 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 internal regulators like formins and Arp2/3 control contact guidance is unknown. In this study, a unique system to assemble aligned collagen fibrils on mica and to transfer them onto controllable substrates is used to probe contact guidance. This fibril alignment system reveals that cytoskeletal regulation through myosin contractility and not receptor expression drives contact guidance ability. Highly contractile cells exhibit high-fidelity contact guidance, weakly contractile cells ignore cues and moderately contractile cells use a mixture of both parallel and perpendicular migration strategies on aligned collagen fibrils. In addition to myosin contractility, formins and Arp2/3 control contact guidance in a reciprocal manner across a variety of cell types. 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 the importance of both myosin-mediated contractility as well as the antagonistic action of formins and Arp2/3 on contact guidance, providing potential targets to tune contact guidance.