Calcium waves and nuclear tension changes coordinate mechanical stress dissipation in locally folded epithelia.

Epithelia are continuously exposed to biomechanical forces such as compression, stretch, and shear stress arising from their dynamic microenvironments. Changes in tension, including stretch, trigger cell rearrangements, divisions, and transcriptional responses until mechanical stress is dissipated. Here, we focus on epithelial folding, a fundamental process by which flat monolayers transform into 3D functional tissues. Using an innovative method for fold generation combined with live imaging, mechanobiology tools, and chemical screening, we uncover the role of calcium waves in the mechanical adaptation of folded epithelia at both tissue and nuclear levels. Folding-associated tension induces nuclear flattening that is recovered within minutes through calcium waves spreading outward across the epithelium. By creating an LBR-overexpressing mutant that relaxes the nuclear envelope, we show that, despite calcium waves, nuclear tension is required for shape recovery via cPLA2-dependent contractility. Our results identify the mechanism of nuclear shape recovery and reveal nuclei as internal tension sensors.