Directed Cell Motility Along Gradients in Extracellular Matrix Fiber Alignment

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Project Summary In native tissue, cell recruitment and positioning are controlled by directed migration, where cells sense multiple guidance cues in their microenvironment and migrate preferentially toward or away from particular signals. Although several types of guidance or "taxis" cues have been identified, the hierarchy between simultaneously presented signals during directed migration remains poorly understood. Dissecting these relationships will help enhance our understanding of cell motility in complex environments with broad implications in therapeutic development to promote or inhibit migratory activity. To expand our knowledge about the cues that promote directed cell migration, we propose a new experimental platform that combines microengineered fiber alignment gradients with controlled soluble biochemical gradients to endothelial, immune, and cancer cell migration within a complex 3D environment. Our platform will allow us to uniquely expose cell populations to a controlled multi-cue 3D environment containing alignment gradients and biochemical gradients to dissect how cells prioritize and respond to simultaneous guidance cues. We hypothesize synergetic (additive) and hierarchal (competitive) relationships between biophysical and biochemical guidance cues that influence directed cell migration. To test this hypothesis, we will carry out the following aims: 1) Quantify migration within a microengineered 3D collagen gel environment with tunable alignment landscapes, 2) Create biochemical gradients and quantify chemotactic responses within 3D gel environments, and 3) Quantify motility responses within combined biophysical and biochemical gradient environments. Success in this project will establish a platform to uniquely study how cells sense, prioritize, and migrate in response to multiple guidance cues (here, biophysical and biochemical gradients), with relevance to early development, immune cell trafficking, vascularization, and cancer invasion.