LAUSR

Beyond the critical role of cell nuclei in gene expression and DNA replication, they also have a significant influence on cell mechanosensation and migration. Nuclear stiffness can impact force transmission and, further, act as a physical barrier to translocation across tight spaces. As such, it is of wide interest to accurately characterize nucleus mechanical behavior. In this study we present the first computational investigation of the in-situ deformation of a heterogeneous cell nucleus. A novel methodology is developed to accurately reconstruct a three-dimensional finite element model of a cell nucleus from confocal microscopy. By incorporating the reconstructed nucleus into a chondrocyte model embedded in pericellular and extracellular matrix, we explore the relationship between spatially heterogeneous nuclear DNA content, shear stiffness and resultant shear strain. We simulate an externally applied shear ECM deformation and compute intra-nuclear strain distributions, which are directly compared to corresponding experimentally measured distributions. Simulations suggest that the mechanical behaviour of the nucleus is highly heterogeneous, with a non-linear relationship between experimentally measure greyscale values and corresponding local shear moduli (μn). Three distinct phases are identified within the nucleus: a low-stiffness mRNA-rich interchromatin phase (0.17kpa≤μn≤0.63kpa), an intermediate-stiffness euchromatin phase (1.48kpa≤μn≤2.7kpa), and a high-stiffness heterochromatin phase (3.58kpa≤μn≤4.0kpa). Our simulations also indicate that disruption of the nuclear envelope associated with lamin-A/C depletion significantly increases nuclear strain in regions of low DNA concentration. We further investigate a phenotypic shift of chondrocytes to fibroblast-like cells, a signature for osteoarthritic cartilage, by increasing the contractility of the actin cytoskeleton to a level associated with fibroblasts. Peak nucleus strains increase by 35% compared to control with the nucleus becoming more ellipsoidal. Our findings may have broad implications for current understanding how local DNA concentrations and associated strain amplification can impact cell mechanotransduction and drive cell behaviour in development, migration, and tumorigenesis.