Abstract
Collective cell migrations are essential in several physiological processes and are driven by both chemical and mechanical cues. The roles of substrate stiffness and confinement on collective migrations have been investigated in recent years, however few studies have addressed how geometric shapes influence collective cell migrations. Here, we address the hypothesis that the relative position of a cell within the confinement influences its motility. Monolayers of two types of epithelial cells—MCF7, a breast epithelial cancer cell line, and MDCK, a control epithelial cell line—were confined within circular, square, and cross-shaped stencils and their migration velocities were quantified upon release of the constraint using particle image velocimetry. The choice of stencil geometry allowed us to investigate individual cell motility within convex, straight and concave boundaries. Cells located in sharp, convex boundaries migrated at slower rates than those in concave or straight edges in both cell types. The overall cluster migration occurred in three phases: an initial linear increase with time, followed by a plateau region and a subsequent decrease in cluster speeds. An acto-myosin contractile ring, present in the MDCK but absent in MCF7 monolayer, was a prominent feature in the emergence of leader cells from the MDCK clusters which occurred every ~125 μm from the vertex of the cross. Further, coordinated cell movements displayed vorticity patterns in MDCK which were absent in MCF7 clusters. We also used cytoskeletal inhibitors to show the importance of acto-myosin bounding cables in collective migrations through translation of local movements to create long range coordinated movements and the creation of leader cells within ensembles. To our knowledge, this is the first demonstration of how bounding shapes influence long-term migratory behaviours of epithelial cell monolayers. These results are important for tissue engineering and may also enhance our understanding of cell movements during developmental patterning and cancer metastasis.
Highlights
The motility of cells is essential in many physiological processes including developmental patterning which guides embryogenesis [1, 2], wound closure [3], immune response by white blood cells [4], and in the uncontrolled movement of metastatic cells in most cancers [5]
Expanding cells in monolayers experience a variety of signals which include mechanical and chemosensory stimuli that synergistically contribute to collective migration behaviors of cells
We investigate the effects of curvatures on migrations of initially constrained MCF7 and MDCK cell monolayers using methods in particle image velocimetry
Summary
The motility of cells is essential in many physiological processes including developmental patterning which guides embryogenesis [1, 2], wound closure [3], immune response by white blood cells [4], and in the uncontrolled movement of metastatic cells in most cancers [5]. Studies showed that geometric constraints dictate how mechanics affects cell growth and apoptosis [9]. Single adherent cells cultured on patterned shapes have cell-matrix adhesions that are mediated by traction forces which vary with surface convexity [10]. These studies suggest that stress fibers within the cell cytoskeleton reorganize to reduce membrane tension effects due to the cell boundary [11]. Geometric constraints influence the cell shape, force generation, and mechanisms for growth and development at the level of individual cells. The effects of geometry on cell clusters and their migration remains poorly understood
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