Glass-like dynamics of collective cell migration

Abstract

Collective cell migration in tissues occurs throughout embryonic development, during wound healing, and in cancerous tumor invasion, yet most detailed knowledge of cell migration comes from single-cell studies. As single cells migrate, the shape of the cell body fluctuates dramatically through cyclic processes of extension, adhesion, and retraction, accompanied by erratic changes in migration direction. Within confluent cell layers, such subcellular motions must be coupled between neighbors, yet the influence of these subcellular motions on collective migration is not known. Here we study motion within a confluent epithelial cell sheet, simultaneously measuring collective migration and subcellular motions, covering a broad range of length scales, time scales, and cell densities. At large length scales and time scales collective migration slows as cell density rises, yet the fastest cells move in large, multicell groups whose scale grows with increasing cell density. This behavior has an intriguing analogy to dynamic heterogeneities found in particulate systems as they become more crowded and approach a glass transition. In addition we find a diminishing self-diffusivity of short-wavelength motions within the cell layer, and growing peaks in the vibrational density of states associated with cooperative cell-shape fluctuations. Both of these observations are also intriguingly reminiscent of a glass transition. Thus, these results provide a broad and suggestive analogy between cell motion within a confluent layer and the dynamics of supercooled colloidal and molecular fluids approaching a glass transition.active matter | cell mechanics | jamming | collective cell dynamics | nonequilibrium T he collective motion of cells within a tissue is a fundamental biological process, both in health and in disease; for example it is essential to embryonic morphogenesis, organ regeneration, and wound repair (1-4). However, while the motion of individual cells is well understood, collective motion of a large number of cells such as in tissues is only understood in specific instances. Moreover, the transition of the motion of single cells to the collective motion of many cells has not been as extensively studied. This transition is well represented by single monolayers of cells; as they become confluent, the motion of the cells becomes increasingly collective, depending on the presence of their neighbors (5). During collective migration within confluent cell layers, cell sheets flow like a fluid yet remain fixed and solidlike at short time scales, with the motion of each cell constrained by the crowding due to its neighbors (5-7). This solid-like character over short times and collective flow over longer times is reminiscent of many crowded particulate systems, which undergo a transition from a supercooled fluid-like state to a glass-like state. By analogy, the collective motion of cells might be described by a similar transition: as cell density rises, neighboring cells restrict the motion of each cell, forcing cells to move in g...

Glassy dynamics in three-dimensional embryonic tissues

“…As we and others [16,52] have noted, active tissues display glassy dynamics: the motion of individual cells is constrained because they are surrounded by tightly packed neighbouring cells that impede their progress. It has been shown that the dynamics in non-biological glassy or jammed materials display universality: dynamical features do not depend on the details of the interactions [53,54].…”

“…Recently, researchers have discovered that some two-dimensional tissues exhibit glassy behaviour [16,17]. In these confluent tissues, individual cells have difficulty moving past one another or exchanging neighbours, resulting in a 'frozen' system with a macroscopic response that is solid-like even on long timescales.…”

Giant fluctuations and structural effects in a flocking epithelium

“…As q is decreased, S 0 (q) is characterised by a pronounced dip, indicating the presence of mesoscopic-scale inhomogeneities in the cell distribution, or clustering [ 32,36]. It is worth noting that this feature cannot appear in equilibrium systems without invoking attractive interactions and for this reason in active systems, one speaks of non-equilibrium clustering.…”

“…RAB5A is a master regulator of the endocytic activity of the cell and it plays an important role in the dissemination of aggressive breast tumours [38,39,40]. In control monolayers, cell density increases due to mitotic division, which causes a near complete kinetic arrest akin to a jamming or rigidity transition [32,41]. We have recently shown that, under these latter conditions [42], the elevation of RAB5A reawakens the motility of kinetically arrested monolayer, by promoting a flocking transition accompanied by the emergence of large-scale, collective, directed migration patterns [43,25].…”

“…In particular, little is known about how the flocking transition affects the structural, physical properties from the microscopic to the mesoscopic scales. If from a biological standpoint, one is interested in better understanding the microscopic features that control the transition to collective motion, the physical properties emerging from the interplay between jamming [32], individual active deformation [24,33,34] non-equilibrium clustering effects 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 A c c e p t e d M a n u s c r i p t [35,36] and the spontaneous symmetry breaking underlying the flocking transition are still not completely understood [37], especially at the finite (and often relatively small!) length and time scales of biological relevance.…”