Fig. 7
Double-feedback loop with YAP activated on NRA regulating EMT. a Simulation result showing that feedback mechanisms lead to emergence of two stable states of high and low YAP activity, indicating epithelial (low Rac1, high E-cadherin, and low YAP) and partial EMT (high Rac1, low E-cadherin, and high YAP) states depending on Rac1 and E-cadherin activity in this system. b Cell migration speed on NRAs with different rigidity values, suggesting that rigidity can regulate the basal rate of YAP activation at different initial distances from the edge of the sheet (all error bars are S.E.M, each number of independently analyzed cells, n, is indicated, * = statistical significance of the speed of cells on NRA in which the rigidities are 10 MPa vs. 1 GPa, *P < 5 × 10−2, **P < 1 × 10−2, and ***P < 5 × 10−3, all two-sided Student’s t-test). c Simulated bimodal distribution of YAP activity as a function of the distance from the sheet edge on NRA substrata of different rigidity values. d Rigidity-dependent YAP localization in nuclei of cells cultured on NRA. Immunofluorescence staining of YAP showing nuclear localization at different distances from the sheet edge on NRAs with different rigidity values (top). Fractions of nuclei displaying different intensities of YAP staining as a function of the distance from the sheet edge on NRA having different rigidity (bottom) (see details in Supplementary discussion and Supplementary Fig. 17). The samples were fixed after 6 h to remove stencils and induce epithelial expansion. e Schematic description of the regulation of EMT by YAP-mediated topographically induced mechanical input, showing full EMT in marginal cells exposed to cell-free areas at the fronts of FLPs, partial EMT in extensive marginal areas, and epithelial organization (no EMT) in the areas most distant from the edge
