384118 Altered Nuclear Rheology and Cellular Force Transduction Highlight Reduced Mechanosensitivity in Premature Aging
Mechanotransduction is the process by which cells respond to external forces, including shear stress from blood flow in endothelial cells and compressive forces in bone. While the mechanisms governing the conversion of mechanical force to biological changes are still being elucidated, recent work suggests mechanical force propagation to the nucleus facilitates the biochemical cascades resulting in changes in gene expression. This idea is supported by known force-induced nuclear changes including reorientation with the direction applied stress, structural reorganization to minimize the force and upregulation of nucleoskeletal proteins.
Here, we investigate cellular mechanisms that influence nuclear structure and rheology using particle tracking microrheology. We identify the role of external force on the underlying chromatin dynamics in primary endothelial cells in response to shear stress and osteocyte cell lines in response to compression. We compare this with the aberrant mechanical response of nuclei in cells from patients with Hutchinson-Gilford progeria syndrome (HGPS), where expression of a mutant form of the lamin A protein, called progerin, results in its accumulation at the nuclear envelope. This disease is frequently used as a model for normal aging due to the accumulation of progerin in cells of healthy aged individuals as well as the presence of atherosclerosis and skeletal degradation in patients with HGPS.
In progerin-expressing cells we observe nuclear stiffening as measured by micropipette aspiration. Our particle tracking measurements reveal this stiffening is isolated to the nucleoskeleton, as the nuclear interior exhibits an effective softening consistent with the reduced heterochromatin typical of the disease pathology. Progerin-expressing cells also exhibit reduced cytoskeletal force transduction to the nuclear interior compared to control cells. This includes a muted intranuclear response to both shear stress and compression in progerin-expressing cells compared to control cells. Given the prevalence HGPS-related defects in the mechanically-responsive tissues, our work suggests that the disease progression may stem directly from reduced mechanical sensitivity in the nuclear interior resulting from nucleoskeletal stiffening with progerin expression. More generally, our work suggests a need for direct mechanical signaling to the nuclear interior for proper mechanotransduction, the absence of which may play a role in the aberrant genetic response to force leading to increased skeletal degradation and cardiovascular dysfunction in HGPS patients and in normal aging.