Abstract
Many collective cell behaviors, including tissue remodeling, morphogenesis and cancer metastasis rely on dynamic mechanical interactions between cells and their neighbors and the extracellular matrix. The lack of quantitative models preclude understanding of how cell-cell and cell-matrix interactions regulate tissue-scale force transmission and tissue morphogenic processes. In this study, we integrate biophysical measurements on model epithelial tissues and computational modelling to explore how cell-level dynamics alter mechanical stress organization at multicellular scales. Using traction force microscopy and micropatterning techniques we show that traction stress distribution in epithelial colonies can vary widely for identical geometries and substrate properties. For colonies with peripheral localization of traction stresses, we recapitulate previously described mechanical behavior of cohesive tissues. Here, a continuum model that treats the tissue as an elastic medium with homogeneous contractility and uniform matrix adhesion captures the localization and magnitude of traction forces over a range of colony geometries. By contrast, highly motile cells within colonies produce traction stresses that fluctuate in space and time. To predict the spatiotemporal patterning of cell-matrix forces, we develop a dynamic vertex model for epithelial monolayers adherent to an elastic substrate. Using this model, we predict that increased cellular motility and reduced intercellular mechanical coupling localize traction stresses in the colony interior, in agreement with our experimental data. Furthermore, the model captures a wide spectrum of localized stress production modes that arise from individual cell activities events including cell division, rotation, and polarized migration. Taken together, our bottom-up model and experiments provide a robust quantitative framework for studying how cell-scale behaviors influences force transmission and relaxation in epithelial tissues.
- TFM
- Traction Force Microscopy
- ECM
- Extracellular Matrix
- MDCK
- Madin-Darby canine kidney
- PAA
- Polyacrylamide
- ZO-1/2 dKD
- Zonula Occludens-1/2 double knockdown