Mechanical Stress dissipation in locally folded epithelia is orchestrated by calcium waves and nuclear tension changes

Epithelia are continuously exposed to a range of biomechanical forces such as compression, stretch and shear stress arising from their dynamic microenvironments and associated to their function. Changes in tension such as stretch are known to trigger cell rearrangements and divisions, and impact cellular transcription until mechanical stress is dissipated. How cells process, adapt and respond to mechanical stress is being intensively investigated. In here we focus on epithelial folding which is the fundamental process of transformation of flatmonolayers into 3D functional tissues. By combining the innovative method for fold generation, live imaging, mechanobiology tools and chemical screening, we uncover the role of calcium waves on mechanical adaptation of folded epithelia that occurs at the tissue and nuclear level. Folding associated tensional load results in the nuclear flattening which is recovered in the time scale of minutes and is dependent on the calcium wave that spread outwards from the channel and across the epithelium. By creating a mutant overexpressing LBR that relaxed nuclear envelope, we demonstrated that despite presence of calcium waves, nuclear tension increase was essential to trigger nuclear shape recovery post folding through the activation of cellular contractility in the cPLA2 dependent manner. Overall our results identify the molecular mechanism for nuclear shape recovery and indicate that mechanical stress dissipation program is activated at the level of nuclei which serve as internal tension sensors.