Abstract
Cells navigate in response to inhomogeneous distributions of extracellular guidance cues. The cellular and molecular mechanisms underlying migration in response to gradients of chemical cues have been investigated for over a century. Following the introduction of micropipettes and more recently microfluidics for gradient generation, much attention and effort was devoted to study cellular chemotaxis, which is defined as guidance by gradients of chemical cues in solution. Haptotaxis, directional migration in response to gradients of substrate-bound cues, has received comparatively less attention; however, it is increasingly clear that in vivo many physiologically relevant guidance proteins – including many secreted cues – are bound to cellular surfaces or incorporated into extracellular matrix and likely function via a haptotactic mechanism. Here, we review the history of haptotaxis. We examine the importance of the reference surface, the surface in contact with the cell that is not covered by the cue, which forms a gradient opposing the gradient of the protein cue and must be considered in experimental designs and interpretation of results. We review and compare microfluidics, contact printing, light patterning, and 3D fabrication to pattern substrate-bound protein gradients in vitro. The range of methods to create substrate-bound gradients discussed herein makes possible systematic analyses of haptotactic mechanisms. Furthermore, understanding the fundamental mechanisms underlying cell motility will inform bioengineering approaches to program cell navigation and recover lost function.
Highlights
Migrating cells rely on extracellular cues to direct motility
We examine the importance of the reference surface, the surface in contact with the cell that is not covered by the cue, which forms a gradient opposing the gradient of the protein cue and must be considered in experimental designs and interpretation of results
Protein gradients exist in two forms in vivo: diffusible, where proteins diffuse away from a source, or substrate-bound, where the cues are fastened either to cell surfaces or to the surrounding extracellular matrix (ECM)
Summary
Migrating cells rely on extracellular cues to direct motility. Cues can influence cellular responses in a wide variety of ways ranging from differences in surface stiffness to direct protein–protein interactions (Lara Rodriguez and Schneider, 2013). Methods to study haptotaxis differentiating chemotactic guidance in response to a soluble cue from haptotactic migration on a substrate-bound cue. In this seminal study, Carter formed gradients of palladium by using a wire as a shadow mask to scatter a gradient of evaporated metal onto acetate-coated glass. Methods to study haptotaxis cells will strongly adhere, and motility will be reduced maximally at the low end of the gradient where a larger proportion of each cell contacts the RS This reasoning holds for cases where high affinity is synonymous with strong adhesion, which is generally but not always the case. It is critical to carefully select and tune the RS, and to interpret cellular responses to a gradient of the protein cue of interest simultaneously in the context of the RS gradient
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