Dynamic biophysical responses of neuronal cell nuclei and cytoskeletal structure following high impulse loading

Cells are continuously exposed to dynamic environmental cues that influence their behavior. Mechani-cal cues can influence cellular and genomic architecture, gene expression, and intranuclear mechanics, providing evidence of mechanosensing by the nucleus, and a mechanoreciprocity between the nucleus and environment. Force disruption at the tissue level through aging, disease, or trauma, propagates to the nucleus and can have lasting consequences on proper functioning of the cell and nucleus. While the influence of mechanical cues leading to axonal damage has been well studied in neuronal cells, the me-chanics of the nucleus following high impulse loading is still largely unexplored. Using an in vitro model of traumatic neural injury, we show a dynamic nuclear behavioral response to impulse stretch (up to 170% strain per second) through quantitative measures of nuclear movement, including tracking of rota-tion and internal motion. Differences in nuclear movement were observed between low and high strain magnitudes. Increased exposure to impulse stretch exaggerated the decrease in internal motion, assessed by particle tracking microrheology, and intranuclear displacements, assessed through high-resolution de -formable image registration. An increase in F-actin puncta surrounding nuclei exposed to impulse stretch additionally demonstrated a corresponding disruption of the cytoskeletal network. Our results show di-rect biophysical nuclear responsiveness in neuronal cells through force propagation from the substrate to the nucleus. Understanding how mechanical forces perturb the morphological and behavioral response can lead to a greater understanding of how mechanical strain drives changes within the cell and nucleus, and may inform fundamental nuclear behavior after traumatic axonal injury.Statement of significance The nucleus of the cell has been implicated as a mechano-sensitive organelle, courting molecular sensors and transmitting physical cues in order to maintain cellular and tissue homeostasis. Disruption of this network due to disease or high velocity forces (e.g., trauma) can not only result in orchestrated biochem-ical cascades, but also biophysical perturbations. Using an in vitro model of traumatic neural injury, we aimed to provide insight into the neuronal nuclear mechanics and biophysical responses at a continuum of strain magnitudes and after repetitive loads. Our image-based methods demonstrate mechanically -induced changes in cellular and nuclear behavior after high intensity loading and have the potential to further define mechanical thresholds of neuronal cell injury.(c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.