Bioengineering Paradigms for Cell Migration in Confined Microenvironments

Cell migration is a fundamental process underlying diverse (patho)physiological phenomena.  Unraveling key, physiologically relevant motility mechanisms is crucial for developing technologies that can control, manipulate, promote or stop cell migration in vivo.  Much of what we know about the mechanisms of cell migration stems from in vitro studies using two-dimensional (2D) substrates.  Cell locomotion in 2D is driven by cycles of actin protrusion, integrin-mediated adhesion and myosin-dependent contraction.  A major pitfall of 2D assays is that they fail to account for the physical confinement that cells encounter within the physiological tissue environment.  The presentation will challenge the conventional wisdom regarding cell motility mechanisms, and show that migration through physically constricted spaces does not require b1 integrin-dependent adhesion or myosin contractility.  Even more surprisingly, confined migration persists even when filamentous actin is disrupted.  Using an integrated experimental and theoretical approach that combines microfluidics, molecular biology, live cell imaging, and mathematical modeling, we present a new paradigm for tumor cell migration in confined spaces that does not depend on actin polymerization or contractility.  This “Osmotic Engine Model” instead relies on directed water permeation through the cell membrane, which is governed by the activity of water channels (aquaporins) and ion channels.  Cells may use this mechanism of migration when migrating along pre-existing tracks between anatomical structures during metastasis in vivo.