Plithotaxis and emergent dynamics in collective cellular migration

Abstract

For a monolayer sheet to migrate cohesively, it has long been suspected that each constituent cell must exert physical forces not only upon its extracellular matrix but also upon neighboring cells. The first comprehensive maps of these distinct force components reveal an unexpected physical picture. Rather than showing smooth and systematic variation within the monolayer, the distribution of physical forces is dominated by heterogeneity, both in space and in time, which emerges spontaneously, propagates over great distances, and cooperates over the span of many cell bodies. To explain the severe ruggedness of this force landscape and its role in collective cell guidance, the well known mechanisms of chemotaxis, durotaxis, haptotaxis are clearly insufficient. In a broad range of epithelial and endothelial cell sheets, collective cell migration is governed instead by a newly discovered emergent mechanism of innately collective cell guidance - plithotaxis.

Fig 1

Traction forces exerted by an MDCK monolayer upon its substrate in the direction perpendicular to the leading edge. Spatial distributions of tractions are heterogeneous, and extreme mechanical events (cells generating very large tractions such as those pointed by arrows) are frequent both at the leading edge and many rows behind it. The circle encloses one of the many cells that appear to be pulling the “wrong” way. Adapted from [17] with permission from Nature Physics.

Fig 2

Cells use a tug-of-war mechanism to integrate local tractions (red) into long-ranged gradients of intra- and inter-cellular tension (blue). Tension in the monolayer reflects the spatial accumulation, or pile-up, of traction forces. Equivalently, the local traction force is the spatial derivative of the intercellular stress.

Fig 3

Fragile cells [47] trekking rugged stress landscape make for resilient monolayers. Cellular migrations (red arrows) follow stress orientations (blue ellipses) over a rugged stress landscape (colored topography denotes local tensile stress; scale bar units: Pa). Cell navigation on this scale – plithotaxis – is innately collective, strongly cooperative, and dynamically glassy. Adapted from [18].