Development, regeneration and cancer involve drastic transitions in tissue morphology. In analogy with the behaviour of inert fluids, some of these transitions have been interpreted as wetting transitions. The validity and scope of this analogy are unclear, however, because the active cellular forces that drive tissue wetting have been neither measured nor theoretically accounted for. Here we show that the transition between two-dimensional epithelial monolayers and three-dimensional spheroidal aggregates can be understood as an active wetting transition whose physics differs fundamentally from that of passive wetting phenomena. By combining an active polar fluid model with measurements of physical forces as a function of tissue size, contractility, cell–cell and cell–substrate adhesion, and substrate stiffness, we show that the wetting transition results from the competition between traction forces and contractile intercellular stresses. This competition defines a new intrinsic length scale that gives rise to a critical size for the wetting transition in tissues, a striking feature that has no counterpart in classical wetting. Finally, we show that active shape fluctuations are dynamically amplified during tissue dewetting. Overall, we conclude that tissue spreading constitutes a prominent example of active wetting—a novel physical scenario that may explain morphological transitions during tissue morphogenesis and tumour progression.
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We thank D. Sarrió and G. Moreno-Bueno for providing the E-cadherin inducible cells; N. Castro for technical assistance; A. Elosegui, V. González, E. Latorre, L. Valon and R. Vincent for stimulating discussions. R.A. thanks G. Torrents for assistance with mathematical details. C.P-G. and R.A. were funded by Fundació ‘La Caixa’. R.A. thanks J. Prost and acknowledges EMBO (Short Term Fellowship ASTF 365-2015), The Company of Biologists (Development Travelling Fellowship DEVTF-151206), and Fundació Universitària Agustí Pedro i Pons for supporting visits to Institut Curie. This work was supported by the Spanish Ministry of Economy and Competitiveness/FEDER (BFU2015-65074-P to X.T., FIS2016-78507-C2-2-P to J.C.), the Generalitat de Catalunya (2014-SGR-927 and CERCA Program to X.T., 2014-SGR-878 to J.C.), the European Research Council (CoG-616480 to X.T.), European Commission (H2020-FETPROACT-01-2016-731957 to X.T.) and Obra Social ‘La Caixa’. IBEC is recipient of a Severo Ochoa Award of Excellence from the MINECO.
Supplementary Video 8 Evolution of traction and monolayer tension fields in islands of different radii. For all sizes, the magnitude of tractions and monolayer tension increase in time as E-cadherin is progressively expressed. Tractions accumulate at the edges of the monolayers, while monolayer tension has a maximum at the centre. Red frames indicate monolayer dewetting.
Supplementary Video 9 Evolution of traction and monolayer tension fields in islands on substrates of different stiffnesses. For monolayer on substrates of Young’s modulus 3 and 12 kPa, tissue forces increase in time, eventually triggering monolayer dewetting. This transition occurs earlier for the softest substrate. For the stiffest substrate (30 kPa), tissue forces keep increasing until the end of the experiment, suggesting that the critical contractility to induce dewetting is not reached. Red frames indicate monolayer dewetting.
Supplementary Video 11 Symmetry breaking of monolayer shape during dewetting. A 200 µm radius cell island divided in 24 sectors. Blue = wetting, red = dewetting. Dewetting starts in diametrically opposed regions of the monolayer edge. Hence, the monolayer loses its initial circular shape and acquires an elliptic-like shape during the early stages of dewetting.