Cell monolayers sense curvature by exploiting active mechanics and nuclear mechanoadaptation

The early development of many organisms involves the folding of cell monolayers, but this behaviour is difficult to reproduce in vitro; therefore, both mechanistic causes and effects of local curvature remain unclear. Here we study epithelial cell monolayers on corrugated hydrogels engineered into wavy patterns, examining how concave and convex curvatures affect cellular and nuclear shape. We find that substrate curvature affects monolayer thickness, which is larger in valleys than crests. We show that this feature generically arises in a vertex model, leading to the hypothesis that cells may sense curvature by modifying the thickness of the tissue. We find that local curvature also affects nuclear morphology and positioning, which we explain by extending the vertex model to take into account membrane–nucleus interactions, encoding thickness modulation in changes to nuclear deformation and position. We propose that curvature governs the spatial distribution of yes-associated proteins via nuclear shape and density changes. We show that curvature also induces significant variations in lamins, chromatin condensation and cell proliferation rate in folded epithelial tissues. Together, this work identifies active cell mechanics and nuclear mechanoadaptation as the key players of the mechanistic regulation of epithelia to substrate curvature.