Investigating the nature of active forces in tissues reveals how contractile cells can form extensile monolayers.

Actomyosin machinery endows cells with contractility at a single-cell level. However, within a monolayer, cells can be contractile or extensile based on the direction of pushing or pulling forces exerted by their neighbours or on the substrate. It has been shown that a monolayer of fibroblasts behaves as a contractile system while epithelial or neural progentior monolayers behave as an extensile system. Through a combination of cell culture experiments and in silico modelling, we reveal the mechanism behind this switch in extensile to contractile as the weakening of intercellular contacts. This switch promotes the build-up of tension at the cell-substrate interface through an increase in actin stress fibres and traction forces. This is accompanied by mechanotransductive changes in vinculin and YAP activation. We further show that contractile and extensile differences in cell activity sort cells in mixtures, uncovering a generic mechanism for pattern formation during cell competition, and morphogenesis.

Bridging microscopic cell dynamics to nematohydrodynamics of cell monolayers.

It is increasingly being realized that liquid-crystalline features can play an important role in the properties and dynamics of cell monolayers. Here, we present a cell-based model of cell layers, based on the phase-field formulation, that connects cell-cell interactions specified at the single cell level to large-scale nematic and hydrodynamic properties of the tissue. In particular, we present a minimal formulation that reproduces the well-known bend and splay hydrodynamic instabilities of the continuum nemato-hydrodynamic formulation of active matter, together with an analytical description of the instability threshold in terms of activity and elasticity of the cells. Furthermore, we provide a quantitative characterisation and comparison of flows and topological defects for extensile and contractile stress generation mechanisms, and demonstrate activity-induced heterogeneity and spontaneous formation of gaps within a confluent monolayer. Together, these results contribute to bridging the gap between cell-scale dynamics and tissue-scale collective cellular organisation.

Sustained Oscillations of Epithelial Cell Sheets.

Morphological changes during development, tissue repair, and disease largely rely on coordinated cell movements and are controlled by the tissue environment. Epithelial cell sheets are often subjected to large-scale deformation during tissue formation. The active mechanical environment in which epithelial cells operate have the ability to promote collective oscillations, but how these cellular movements are generated and relate to collective migration remains unclear. Here, combining in vitro experiments and computational modeling, we describe a form of collective oscillations in confined epithelial tissues in which the oscillatory motion is the dominant contribution to the cellular movements. We show that epithelial cells exhibit large-scale coherent oscillations when constrained within micropatterns of varying shapes and sizes and that their period and amplitude are set by the smallest confinement dimension. Using molecular perturbations, we then demonstrate that force transmission at cell-cell junctions and its coupling to cell polarity are pivotal for the generation of these collective movements. We find that the resulting tissue deformations are sufficient to trigger osillatory mechanotransduction of YAP within cells, potentially affecting a wide range of cellular processes.

Emergence of Active Nematic Behavior in Monolayers of Isotropic Cells.

There is now growing evidence of the emergence and biological functionality of liquid crystal features, including nematic order and topological defects, in cellular tissues. However, how such features that intrinsically rely on particle elongation emerge in monolayers of cells with isotropic shapes is an outstanding question. In this Letter, we present a minimal model of cellular monolayers based on cell deformation and force transmission at the cell-cell interface that explains the formation of topological defects and captures the flow-field and stress patterns around them. By including mechanical properties at the individual cell level, we further show that the instability that drives the formation of topological defects, and leads to active turbulence, emerges from a feedback between shape deformation and active driving. The model allows us to suggest new explanations for experimental observations in tissue mechanics, and to propose designs for future experiments.

Active matter invasion.

Biologically active materials such as bacterial biofilms and eukaryotic cells thrive in confined micro-spaces. Here, we show through numerical simulations that confinement can serve as a mechanical guidance to achieve distinct modes of collective invasion when combined with growth dynamics and the intrinsic activity of biological materials. We assess the dynamics of the growing interface and classify these collective modes of invasion based on the activity of the constituent particles of the growing matter. While at small and moderate activities the active material grows as a coherent unit, we find that blobs of active material collectively detach from the cohort above a well-defined activity threshold. We further characterise the mechanical mechanisms underlying the crossovers between different modes of invasion and quantify their impact on the overall invasion speed.

Fluctuation-induced dynamics of nematic topological defects.

Topological defects are increasingly being identified in various biological systems, where their characteristic flow fields and stress patterns are associated with continuous active stress generation by biological entities. Here, using numerical simulations of continuum fluctuating nematohydrodynamics, we show that even in the absence of any specific form of active stresses associated with self-propulsion, mesoscopic fluctuations in either orientational alignment or hydrodynamics can independently result in flow patterns around topological defects that resemble the ones observed in active systems. Our simulations further show the possibility of extensile- and contractile-like motion of fluctuation-induced positive half-integer topological defects. Remarkably, isotropic stress fields also reproduce the experimentally measured stress patterns around topological defects in epithelia. Our findings further reveal that extensile- or contractile-like flow and stress patterns around fluctuation-induced defects are governed by passive elastic stresses and flow-aligning behavior of the nematics.

Active inter-cellular forces in collective cell motility.

The collective behaviour of confluent cell sheets is strongly influenced both by polar forces, arising through cytoskeletal propulsion, and by active inter-cellular forces, which are mediated by interactions across cell-cell junctions. We use a phase-field model to explore the interplay between these two contributions and compare the dynamics of a cell sheet when the polarity of the cells aligns to (i) their main axis of elongation, (ii) their velocity and (iii) when the polarity direction executes a persistent random walk. In all three cases, we observe a sharp transition from a jammed state (where cell rearrangements are strongly suppressed) to a liquid state (where the cells can move freely relative to each other) when either the polar or the inter-cellular forces are increased. In addition, for case (ii) only, we observe an additional dynamical state, flocking (solid or liquid), where the majority of the cells move in the same direction. The flocking state is seen for strong polar forces, but is destroyed as the strength of the inter-cellular activity is increased.