Correlations between altered nuclear shape and disease are empirically observed, but the causes of nuclear dysmorphisms are poorly understood. The nucleoskeleton, which provides the majority of the mechanical stability of the nucleus, is composed primarily of intermediate filaments of lamin proteins. The nucleoskeleton forms a mostly-planar network between the inner nuclear membrane and chromatin. It is unclear if blebs and larger scale changes in nuclear morphology are consequences of reorganization of the nucleoskeleton alone or of other cellular processes. To test this, we computationally recapitulate the lamina network using a mechanical network model created as a network of Hookean springs. A- and B-type lamin filaments were distributed over a spherical surface into distinct networks linked to one another by lamin-associated proteins. Iterative force-based adjustment of the network structure, together with a stochastically modified Bell model of bond breakage and formation, simulates nucleoskeleton reorganization with blebs. The rate of bleb retraction into the nucleus depends on both initial size of the bleb and number of networks being deformed. Our results show that induced blebs are more stable when only one filament component is deformed or when the networks have no interconnections. Also, the kinetics of retraction is influenced by the composition of the bleb. These results match with our experiments and others.
Mechanotransduction of extracellular stimuli into the chromatin located in the cell nucleus and overall cell mechanics may require the physical support of structures of A-type lamins. Several cellular pathologic phenotypes and phases of stem cell differentiation involve regulation and reorganization of A-type lamins. Here is presented a study of changes in cell mechanics associated to the reorganization of nuclear structures consequent to knockdown of A-type lamins. Transient dysmophism of the cell nucleus is observed during knockdown of A-type lamins, which seems to be driven by inner cellular forces resultant of cytoskeletal and chromatin structural reorganization.
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