Large-scale curvature sensing by epithelial monolayers depends on active cell mechanics and nuclear mechanoadaptation

While many tissues fold in vivo in a highly reproducible and robust way, epithelial folds remain difficult to reproduce in vitro. The current challenge is therefore to form in vitro folded epithelial tissues for understanding how assembly of epithelial cells detect and integrate topographical cues in terms of positive and negative curvatures.

By growing MDCK cells on wavy hydrogels, we formed in vitro folded epithelial tissues to study how concave and convex curvatures affect cellular and nuclear shape.

We find that the substrate curvature leads to thicker epithelial zones in the valleys and thinner ones on the crest, a feature which we show generically arises in vertex model, leading us to hypothesize that curvature sensing could arise from resulting density/thickness changes. Consequently, we find that the spatial distribution of Yes associated proteins (YAP), the main transcriptional effector of the Hippo signaling pathway, is modulated in folded epithelial tissues according to the resulting thickness modulation, an effect that disappears at high cell density.

Additionally, we show that these curvatures lead to significant modulations of the nuclear morphology and positioning, where thickness modulation generically translate into the corresponding changes in nuclear aspect ratio and position.

Finally, we showed that these deformations are also associated with changes in the relative abundance of A- versus B-type lamins, significant chromatin condensation and to lower cell proliferation rate.