Nature of active forces in tissues: how contractile cells can form extensile monolayers

Abstract

Actomyosin machinery endows cells with contractility at a single cell level. However, at a tissue scale, cells can show either contractile or extensile behaviour based on the direction of pushing or pulling forces due to neighbour interactions or substrate interactions. Previous studies have shown that a monolayer of fibroblasts behaves as a contractile system while a monolayer of epithelial cells or neural crest cells behaves as an extensile system. How these two contradictory sources of force generation can coexist has remained unexplained. Through a combination of experiments using MDCK (Madin Darby Canine Kidney) cells, and in-silico modeling, we uncover the mechanism behind this switch in behaviour of epithelial cell monolayers from extensile to contractile as the weakening of intercellular contacts. We find that this switch in active behaviour also promotes the buildup of tension at the cell substrate interface through an increase in actin stress fibers and higher traction forces. This in turn triggers a mechanotransductive response in vinculin translocation to focal adhesion sites and YAP (Yes-associated protein) transcription factor activation. Our studies also show that differences in extensility and contractility act to sort cells, thus determining a general mechanism for mechanobiological pattern formation during cell competition, morphogenesis and cancer progression.

Tight junction ZO proteins maintain tissue fluidity, ensuring efficient collective cell migration

“…This tug-of-war mechanism, where phase separation happens and ‘winner’ cells stretch out ‘loser’ cells is in line with quite similar co-culture experiments of contractile and non-contractile cells by Ladoux and co-workers. [47] Essentially, we observe the same contractility-driven phase separation as a consequence of activity differences rather than differential adhesion between the two cell types. The observations of uncontrolled proliferation and mechanical imbalances are in line with the idea that TJs are both biological signaling hubs [53,54] and mechanical sensors.…”

“…This is distinct from phase separation based on differential adhesion between two cell types and has first been reported by Balasubramaniam et al using wildtype MDCK II cells mixed with more contractile E-cadherin KO cells. [47] The majority of dKD cells within this mixture is now capable of adopting the preferred, condensed and highly contractile phenotype, while the wildtype cells maintain their extensile behavior. The presence of this jammed phase eventually slows down collective migration of the whole layer and the wildtype.…”

Tight Junction ZO Proteins Maintain Tissue Fluidity, Ensuring Efficient Collective Cell Migration

“…This tug‐of‐war mechanism, where phase separation happens and “winner” cells stretch out “loser” cells is in line with quite similar co‐culture experiments of contractile and non‐contractile cells by Ladoux and co‐workers. [ 47 ] Essentially, we observe a similar contractility‐driven phase separation as a consequence of activity differences rather than differential adhesion between the two cell types.…”

Active forces in confluent cell monolayers

“…Moreover, motile topological defects, regions where the long axes of the cells take comet or trefoil-like configurations (Fig. 1(b)(c)), have been identified in several confluent cell layers [23][24][25][26]. This is reminiscent of active turbulence, which is the dynamical behaviour of many active nematic materials, such as suspensions of microswimmers [27,28] or microtubules driven by motor proteins [27].…”