Fundamental biological processes including morphogenesis, tissue repair and tumour metastasis require collective cell motions 1-3 , and to drive these motions cells exert traction forces on their surroundings 4 . Current understanding emphasizes that these traction forces arise mainly in 'leader cells' at the front edge of the advancing cell sheet 5-9 . Our data are contrary to that assumption and show for the first time by direct measurement that traction forces driving collective cell migration arise predominately many cell rows behind the leading front edge and extend across enormous distances. Traction fluctuations are anomalous, moreover, exhibiting broad non-Gaussian distributions characterized by exponential tails 10-12 . Taken together, these unexpected findings demonstrate that although the leader cell may have a pivotal role in local cell guidance, physical forces that it generates are but a small part of a global tug-of-war involving cells well back from the leading edge.The single adherent cell moves by the action of two synchronized cycles, one involving extension and contraction of its cytoskeleton and the other involving formation and detachment of its adhesions 13,14 . Although this complex process remains a matter of intense research [14][15][16]

Cells comprising a tissue migrate as part of a collective. How collective processes are coordinated over large multi-cellular assemblies has remained unclear, however, because mechanical stresses exerted at cell-cell junctions have not been accessible experimentally. We report here maps of these stresses within and between cells comprising a monolayer. Within the cell sheet there arise unanticipated fluctuations of mechanical stress that are severe, emerge spontaneously, and ripple across the monolayer. This stress landscape becomes increasingly rugged, sluggish, and cooperative with increasing system density. Within that landscape, local cellular migrations follow local orientations of maximal principal stress. Migrations of both endothelial and epithelial monolayers conform to this behavior, as do breast cancer cell lines before but not after the epithelial-mesenchymal transition. Collective migration in these diverse systems is seen to be governed by a simple but unifying physiological principle: neighboring cells join forces to transmit appreciable normal stress across the cell-cell junction, but migrate along orientations of minimal intercellular shear stress.

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...

The reversible fluid-solid transition in granular gels enables the three-dimensional writing of soft, delicate, macroscopic structures with microscopic detail.

Bacterial biofilms are organized communities of cells living in association with surfaces. The hallmark of biofilm formation is the secretion of a polymeric matrix rich in sugars and proteins in the extracellular space. In Bacillus subtilis, secretion of the exopolysaccharide (EPS) component of the extracellular matrix is genetically coupled to the inhibition of flagella-mediated motility. The onset of this switch results in slow expansion of the biofilm on a substrate. Different strains have radically different capabilities in surface colonization: Flagella-null strains spread at the same rate as wild type, while both are dramatically faster than EPS mutants. Multiple functions have been attributed to the EPS, but none of these provides a physical mechanism for generating spreading. We propose that the secretion of EPS drives surface motility by generating osmotic pressure gradients in the extracellular space. A simple mathematical model based on the physics of polymer solutions shows quantitative agreement with experimental measurements of biofilm growth, thickening, and spreading. We discuss the implications of this osmotically driven type of surface motility for nutrient uptake that may elucidate the reduced fitness of the matrix-deficient mutant strains.collective motility | gel swelling | surface translocation | bacterial biofilm | polymeric secretion B acterial biofilms are heterogeneous populations of differentiated bacteria that live in association with surfaces and exhibit a remarkable degree of spatio-temporal organization (1-3). The formation of a mature biofilm occurs in several stages, starting from the attachment of a single cell to a solid substrate. When cells commit to the surface, a protein-and sugar-rich polymeric extracellular matrix (ECM) is secreted in the extracellular space and holds the community together. Several different functions have been attributed to the ECM, ranging from protection to mechanical integrity and reserve of nutrient (4, 5). At the same time, flagella are downregulated, and most cells lose their individual motility. For the Gram-positive soil bacterium Bacillus subtilis the loss of flagella-mediated motility is genetically coupled to the production of extracellular matrix (6-10). This switch results in a slow kind of surface motility that allows the biofilm to spread outward on the substrate. Although spreading has been attributed to a qualitative concept of "pushing" associated with biomass growth, the physical force generating mechanism that drives biofilm expansion outward across a surface is not known. One intriguing possibility is the potential contribution of the ECM to biofilm growth; the ECM is a highly visco-elastic and sticky substance, and it might be expected to hinder expansion rather than facilitate it (4, 5). However, the ECM clearly plays a crucial role in biofilm, and its possible effect in the actual expansion of the biofilms has never been investigated.Here, we demonstrate that, in the first 24 h of biofilm development, extracellular matrix product...