Abstract
Large nuclear deformations during migration through confined spaces have been associated with nuclear membrane rupture and DNA damage. However, the stresses associated with nuclear damage remain unclear. Here, using a quasi-static plane strain finite element model, we map evolution of nuclear shape and stresses during confined migration of a cell through a deformable matrix. Plastic deformation of the nucleus observed for a cell with stiff nucleus transiting through a stiffer matrix lowered nuclear stresses, but also led to kinking of the nuclear membrane. In line with model predictions, transwell migration experiments with fibrosarcoma cells showed that while nuclear softening increased invasiveness, nuclear stiffening led to plastic deformation and higher levels of DNA damage. In addition to highlighting the advantage of nuclear softening during confined migration, our results suggest that plastic deformations of the nucleus during transit through stiff tissues may lead to bending-induced nuclear membrane disruption and subsequent DNA damage.
Highlights
We show that plastic or permanent nuclear deformation which is necessary for successful migration through small pores in stiff matrices, leads to bending of the nuclear membrane
Compression of the cell during confined migration is associated with compression of the nucleus with the extent of cytoplasmic/nuclear deformations dictated by their mechanical properties in relation to that of the surrounding tissues
For studying dynamics of confined migration, a finite element model was developed wherein physical properties of cell membrane, cell cytoplasm, and nucleus were taken into account
Summary
Computational methodsFor studying dynamics of confined cell migration, a plane strain finite element (FE) model of the system was created in ABAQUS/Explicit. Numerical techniques (e.g., Runge-Kutta technique) are used to arrive at an approximate solution to an equation of the general form [K]{u} = {F} This is analogous to a Hookean spring with [K] being a matrix representing spring stiffness, {u} representing a displacement vector and {F} denoting a vector of applied force. This equation is computed at each node of each polygonal element that the object is made of (S1 Text). Cells were plated sparsely on glass coverslips coated with rat-tail collagen I (Cat # 3867, Sigma) at a coating density of 10 μg/cm. 105 cells were seeded on the upper chamber of 24 well plate cell culture inserts containing 3 μm pores (Cat # 353096, Merck). The upper chambers were filled with plain DMEM supplemented with drugs and the lower chambers filled with DMEM containing 20% FBS
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