Compressing cell nuclei: From nonlinear mechanics to nontrivial shapes

Abnormal nuclear shapes are a feature of many human pathologies, such as metastatic cancer, Hutchinson-Gilford progeria syndrome (rapid aging), and mandibulofacial dysplasia disorder. Understanding these nuclear aberrations from a mechanical point of view may reveal physical mechanisms of cell nuclear function and suggest new approaches to clinical therapies. Recent experimental studies show that the nucleus takes irregular shapes called blebs and mechanically stiffens under compression. We have developed a Brownian-dynamics-based model of a nucleus subjected to uniaxial compression. Our model consists of a polymeric protein shell called the lamina, with a chain of monomeric subunits representing chromatin inside the shell. Chromatin binds to itself randomly via crosslinkers and to the lamina via linkages. Extensile and contractile motors remodeling the chromatin represent the ATP-driven activity in the nucleus. We find that with fast compression in the low-strain regime, the nucleus demonstrates compression stiffening behavior. We also observe localized bulges on the nuclear surface, indicating the possible formation of blebs. For the same strains, with slow compression, the nucleus shows a more ellipsoidal shape, with fewer bulges as compared to fast compression. Our results suggest that during fast compression cycles, compressive forces do not propagate far into the nucleus. However, with slow compression, forces can propagate further which leads chromatin to rearrange itself to accommodate the high strains. Our model captures nuclear compression stiffening and shows how different nuclear morphologies arise in response to applied forces.