This study uses experiments and biophysical modeling to examine the response and adaptation of cells to nanoscale topography of surfaces. It is shown that cytoskeletal assembly and nuclear localization of transcription regulatory factors such as yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) can be tuned by nanoscale membrane curvature and nuclear deformation and rupture due to substrate nanotopography.
Abstract
Nuclear translocation of the transcription regulatory proteins yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) is a critical readout of cellular mechanotransduction. Recent experiments have demonstrated that cells on substrates with well-defined nanotopographies demonstrate mechanoadaptation through a multitude of effects – increased integrin endocytosis as a function of nanopillar curvature, increased local actin assembly on nanopillars but decreased global cytoskeletal stiffness, and enhanced nuclear deformation. How do cells respond to local nanotopographical cues and integrate their responses across multiple length scales? This question is addressed using a biophysical model that incorporates plasma membrane (PM) curvature-dependent endocytosis, PM curvature-sensitive actin assembly, and stretch-induced opening of nuclear pore complexes (NPCs) in the nuclear envelope (NE). This model recapitulates lower levels of global cytoskeletal assembly on nanopillar substrates, which can be partially compensated for by local actin assembly and NE indentation, leading to enhanced YAP/TAZ transport through stretched NPCs. Using cell shapes informed by electron micrographs and fluorescence images, the model predicts lamin A and F-actin localization around nanopillars, in agreement with experimental measurements. Finally, simulations predict nuclear accumulation of YAP/TAZ following rupture of the NE and this is validated by experiments. Overall, this study indicates that nanotopography tunes mechanoadaptation through both positive and negative feedback on mechanotransduction.
Advanced Science, EarlyView. Read More
