Abstract
Keratocytes are fast-moving cells in which adhesion dynamics are tightly coupled to the actin polymerization motor that drives migration, resulting in highly coordinated cell movement. We have found that modifying the adhesive properties of the underlying substrate has a dramatic effect on keratocyte morphology. Cells crawling at intermediate adhesion strengths resembled stereotypical keratocytes, characterized by a broad, fan-shaped lamellipodium, clearly defined leading and trailing edges, and persistent rates of protrusion and retraction. Cells at low adhesion strength were small and round with highly variable protrusion and retraction rates, and cells at high adhesion strength were large and asymmetrical and, strikingly, exhibited traveling waves of protrusion. To elucidate the mechanisms by which adhesion strength determines cell behavior, we examined the organization of adhesions, myosin II, and the actin network in keratocytes migrating on substrates with different adhesion strengths. On the whole, our results are consistent with a quantitative physical model in which keratocyte shape and migratory behavior emerge from the self-organization of actin, adhesions, and myosin, and quantitative changes in either adhesion strength or myosin contraction can switch keratocytes among qualitatively distinct migration regimes.
Highlights
Motile cell shape and speed emerge from nanometer-scale interactions among constituent elements, including the actin network, myosin, adhesions, and the cell membrane [1]
Cell migration is important for many biological processes: white blood cells chase down and kill bacteria to guard against infection, epithelial cells crawl across open wounds to promote healing, and embryonic cells move collectively to form organs and tissues during embryogenesis
We have used a simple cell type, the fish epithelial keratocyte, as a model system to investigate the manner in which these forces are integrated to give rise to large-scale emergent properties such as cell shape and movement
Summary
Motile cell shape and speed emerge from nanometer-scale interactions among constituent elements, including the actin network, myosin, adhesions, and the cell membrane [1]. Cells are thought to transmit forces to the underlying substrate via a mechanism in which adhesions act as ‘‘molecular clutches’’ that couple the actin network to the substrate [6] This physical linkage creates a frictional slippage interface that balances myosinmediated contractile forces [7,8,9,10,11]. As the amount of myosin contraction, and the amount of force transmitted by engaged clutches, increases, the off-rate constant for the clutches increases exponentially [12], reducing the average lifetime for the population of clutches This effectively decreases the coefficient of friction between the cell and the substrate, reducing the amount of traction force that can be transmitted to the substrate and increasing actin retrograde flow. The dynamics of the cell boundary, and cell shape, are determined in part by adhesion- and myosin-dependent friction and retrograde flow rates: high friction stabilizes actin-driven protrusion of the cell boundary, whereas low friction results in retrograde flow of the actin network and retraction of the cell boundary
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