Giant fluctuations and structural effects in a flocking epithelium

Abstract

Abstract. Epithelial cells cultured in a monolayer are very motile in isolation but reach a near-jammed state when mitotic division increases their number above a critical threshold. We have recently shown that a monolayer can be reawakened by over-expression of a single protein, RAB5A, a master regulator of endocytosis. This reawakening of motility was explained in term of a flocking transition that promotes the emergence of a large-scale collective migratory pattern. Here we focus on the impact of this reawakening on the structural properties of the monolayer. We find that the unjammed monolayer is characterised by a fluidisation at the single cell level and by enhanced non-equilibrium large-scale number fluctuations at a larger length scale. Also with the help of numerical simulations, we trace back the origin of these fluctuations to the selfpropelled active nature of the constituents and to the existence of a local alignment mechanism, leading to the spontaneous breaking of the orientational symmetry.

Active glasses

“…It remains to be established whether two-body liquid-state-theory concepts of (active or passive) particles will also be meaningful to describe the properties of confluent and deformable living cells. One of the first steps in this direction was recently taken by Giavazzi et al [95] to relate the static structure factor of cell nuclei to the flocking behavior of an epithelial monolayer.…”

Quantitative Assessment of the Toner and Tu Theory of Polar Flocks

“…But the TT papers remain influential even though they deal with the limit case of dilute, aligning, dry active matter, which usually consists of self-propelled particles subjected to local alignment in the absence of any surrounding fluid [15]. In particular, the TT theory (and related works by Ramaswamy et al) predicted what has become one of the most popular features in active matter studies, the presence, in orientationally-ordered phases, of "giant number fluctuations" where the variance of the number of particles in sub-systems of increasing size scales faster than the mean [16][17][18][19][20][21][22][23][24].…”

“…Over the years, numerous numerical and experimental works have tried to verify the TT results, but the evidence presented has been restricted to a limited range of scales [25] and/or isotropic measures averaged over all spatial directions that cannot resolve individual scaling exponents [19,23,26], resulting in exponent values that could only be deemed compatible with the TT predictions. This situation was satisfactory as long as the TT theory was believed, as claimed in the early papers [2,27], to be 'exact at all orders' in 2D, the dimension of choice of most works.…”

Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma

“…It is likely that additional, not yet identified substrates are phosphorylated by endosomal ERK1/2. Indeed, reawakening of motility in jammed epithelia requires perturbations of different cellular and supra-cellular pathways and properties (including cell-cell adhesion, surface tension 79 and monolayer rigidity 33 for optimal long-range force transmission 80 , volume and density fluctuations 32, 81 ), which are all required to initiate a mode of locomotion that combines large scale correlation length with increased local cell arrangement typical of fluidized RAB5A tissues. This notwithstanding, impairing protrusion extension impedes the emergence of persistent flocking motion and abrogates the re-awakening of motility, pointing to a major role of the protrusion extension mechanism in setting the local directionality of the flocking motion.…”

“…RAB5A further promotes millimetres-scale, ballistic locomotion of multicellular streams by augmenting the extension of oriented and persistent RAC1-driven, protrusions 30 . These effects combine to endow monolayers with a flocking fluid mode of motion, which is explained in numerical simulations in terms of large scale coordinated migration and local unjamming, driven by an increased capability of each individual cell to align its velocity to the one of the surrounding group 30-32 . Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogated RAB5A-induced collective motility, suggesting that perturbations of trafficking processes impacting on different signalling and biomechanical pathways are necessary for the JUT.…”