Shear stress induced nuclear shrinkage through activation of Piezo1 channels in epithelial cells

The cell nucleus responds to mechanical cues with changes in size, morphology, and motility. Previous work showed that external forces couple to nuclei through the cytoskeleton network, but we show here that changes in nuclear shape can be driven solely by calcium levels. Fluid shear stress applied to MDCK cells caused the nuclei to shrink through a Ca 2+ dependent signaling pathway. Inhibiting mechanosensitive Piezo1 channels with GsMTx4 prevented nuclear shrinkage. Piezo1 knockdown also significantly reduced the nuclear shrinkage. Activation of Piezo1 with the agonist Yoda1 caused similar nucleus shrinkage without shear stress. These results demonstrate that Piezo1 channel is a key element for transmitting shear force input to nuclei. To ascertain the relative contributions of Ca 2+ to cytoskeleton perturbation, we examined the F-actin reorganization under shear stress and static conditions, and showed that reorganization of the cytoskeleton is not necessary for nuclear shrinkage. These results emphasize the role of the mechanosensitive channels as primary transducers in force transmission to the nucleus.