Emergence of single cell mechanical behavior and polarity within epithelial monolayers drives collective cell migration

Abstract

The directed migration of cell collectives is essential in various physiological processes, such as epiboly, intestinal epithelial turnover, and convergent extension during morphogenesis as well as during pathological events like wound healing and cancer metastasis 1,2 . Collective cell migration leads to the emergence of coordinated movements over multiple cells. Our current understanding emphasizes that these movements are mainly driven by large-scale transmission of signals through adherens junctions 3,4 . In this study, we show that collective movements of epithelial cells can be triggered by polarity signals at the single cell level through the establishment of coordinated lamellipodial protrusions. We designed a minimalistic model system to generate one-dimensional epithelial trains confined in ring shaped patterns that recapitulate rotational movements observed in vitro in cellular monolayers and in vivo in genitalia or follicular cell rotation 5-7 . Using our system, we demonstrated that cells follow coordinated rotational movements after the establishment of directed Rac1-dependent polarity over the entire monolayer. Our experimental and numerical approaches show that the maintenance of coordinated migration requires the acquisition of a front-back polarity within each single cell but does not require the maintenance of cell-cell junctions. Taken together, these unexpected findings demonstrate that collective cell dynamics in closed environments as observed in multiple in vitro and in vivo situations 5,6,8,9 can arise from single cell behavior through a sustained memory of cell polarity. 3 Main TextThe ability of cells to migrate collectively is crucial in shaping organisms during the complex morphogenetic events of development, and for several physiological and pathological events like wound healing and cancer metastasis 1,2 . Single cell migration is associated with a front-back polarity that includes the formation of a lamellipodial structure at the leading edge 10,11 . Even though this mode of migration is still under intense research 12 , it is now clearly established that the protrusive activity driven by actin polymerization at the cell front leads to forward movement in a directional and persistent fashion 13,14 . Collective movements require a higher degree of complexity and are thus less well understood. Collectively migrating cells display a complex range of front-rear polarization and mechanical coupling behaviors that depend on their position within the migrating monolayer 15,16 . Collective migration behaviors occur under a broad range of external constraints that induce the appearance of highly motile mesenchymal-like 'leader' cells 17 , the local guidance of small cohorts of 'follower' cells 18 , and large-scale movements within the bulk of cell monolayers 19 . The emergence of these polarized cellular assemblies thus results from the integration of intra-and extra-cellular biomechanical cues that cooperate to steer and maintain the migration of cohesive groups 20 .Both in vivo and in v...

One dimensional cell motility patterns

“…In addition, the model makes predictions that can motivate future experimental exploration. Finally, having a model for single-cell motility can serve as the basis for the description of collective cell migration [30], which goes beyond treatments of the cells as simplified self-propelled particles. In Eqs.1,2 the parameters α and γ should be multiplied by a factor of r/(r + r 0 ), but throughout the main text (Fig.…”

Dispersal and organization of polarized cells: non-linear diffusion and cluster formation without adhesion

“…Unfortunately, the precise details of collective cell dynamics remains unclear at this point due to the rich framework of interactions mediated by cell-cell junctions, adhesion molecules, or emergent dynamical phenomena [9]. For instance, it has been observed experimentally that directional persistence prompts coordinated migration patterns even in the absence of cell-cell junctions in low-dimensional systems [10], striking the stance that explicit interactions are necessary for collective motions of cells. On the other hand, our understanding of the molecular and biological processes responsible for the movement of isolated cells have vastly improved in the past decade [9,11,12].…”