A predictive mechanochemical modeling framework for the deformation and remodeling of the nuclear lamina

Nuclear envelope (NE) deformation and rupture are common in cell spreading and migration in a variety of microenvironments and lead to marked changes in nucleocytoplasmic transport. Predicting responses to different mechanochemical cues that are transmitted to the nucleus remains an open problem in the field of mechanomedicine. We have developed a predictive modeling framework to examine how nuclear deformation on substrates with different nanotopographies influences nucleocytoplasmic transport and rearrangement of the nuclear lamina. Using the finite element method, we simulated nuclear compression by the perinuclear actin cap on substrates with arrays of nanopillars, modeling the NE-lamin composite as a nonlinear elastic structure and coupling deformations to a biochemical model of lamin remodeling and nucleocytoplasmic transport. Our simulations generated nuclear morphologies that agreed well with our experimental measurements and predicted that the regions of highest NE stretch are adjacent to cell-nanopillar contacts, leading to maximized NE tension on nanopillars spaced by 5-7 microns. We then considered the effects on transport of YAP/TAZ and remodeling of the nuclear lamina. In our model, increased nuclear flattening facilitated YAP/TAZ nuclear localization due to NPC dilation. We validated these predictions by measuring nuclear YAP and lamin localization in subsequent experiments. Finally, we considered the implications of our model for NE rupture. We found that substrate nanotopography and lamin abundance were both strong predictors of the force load in the nuclear lamina and the resulting rupture likelihood. We validated this prediction in subsequent experiments with lamin-depleted U2OS cells, establishing the central importance of lamin transport and microenvironment nanotopography in nuclear mechanotransduction.