Is there a universal mechanism of cell alignment in response to substrate topography?

Cell alignment and elongation in the direction of anisotropic and aligned topographies are key manifestations of cellular contact guidance and are observed in many cell types. Whether this observation occurs through a universal mechanism remains to be established. In this Views article, we begin by presenting the most widely accepted model of topography-driven cell alignment which posits that anisotropic topographies impose lateral constraints on the growth of focal adhesions and actin stress fibers, thereby driving anisotropic force generation and cellular elongation and alignment. We then discuss particular scenarios where alternative or complementary mechanisms of cell alignment appear to be at play. These include the cases of specific cell types such as amoeboid-like cells and neurons as well as certain topography sizes. Finally, we review the role of the actin cytoskeleton in modulating topography-driven cell alignment and underscore the need for elucidating the role that other cytoskeletal elements play. We close by identifying key open questions the responses to which will significantly enhance our understanding of the role of cellular contact guidance in health and disease.