Viscous shaping of the compliant cell nucleus

Abstract

The cell nucleus is commonly considered to be a stiff organelle that mechanically resists changes in shape, and this resistance is thought to limit the ability of cells to migrate through pores or spread on surfaces. Generation of stresses on the cell nucleus during migration and nuclear response to these stresses is fundamental to cell migration and mechano-transduction. In this Perspective, we discuss our previous experimental and computational evidence that supports a dynamic model, in which the soft nucleus is irreversibly shaped by viscous stresses generated by the motion of cell boundaries and transmitted through the intervening cytoskeletal network. While the nucleus is commonly modeled as a stiff elastic body, we review how nuclear shape changes on the timescale of migration can be explained by simple geometric constraints of constant nuclear volume and constant surface area of the nuclear lamina. Because the lamina surface area is in excess of that of a sphere of the same volume, these constraints permit dynamic transitions between a wide range of shapes during spreading and migration. The excess surface area allows the nuclear shape changes to mirror those of the cell with little mechanical resistance. Thus, the nucleus can be easily shaped by the moving cell boundaries over a wide range of shape changes and only becomes stiff to more extreme deformations that would require the lamina to stretch or the volume to compress. This model explains how nuclei can easily flatten on surfaces during cell spreading or elongate as cells move through pores until the lamina smooths out and becomes tense.

Lamin A/C mediated invaginations in the nuclear surface allow the nucleus to pass unimpeded through a dense array of fiber-like obstacles

“…These differences in shape can be explained by a mechanical resistance to a strain of the nuclear interior on the shorter time scale but a uniform nuclear pressure balanced by surface tension on the longer time scale. This explanation is consistent with the notion that any mechanical energy stored in the strained nuclear interior dissipates on the time scale of migration such that only the surface tension and the resistance of the nucleus to volume change (i.e., nuclear pressure) govern nuclear deformation in response to external forces on this time scale (Lele et al, 2018, Dickinson et al, 2022).…”

“…It is well known that on short time scales, nuclei can behave visco-elastically (Guilak et al, 2000, Dahl et al, 2005, Pajerowski et al, 2007, Ivanovska et al, 2010, Swift et al, 2013, Shin et al, 2013, Harada et al, 2014, Stephens et al, 2017, Wintner et al, 2020, Zuela-Sopilniak et al, 2020). However, we have previously shown that on the time scale of cell migration, nuclear deformations that occur during migration are not elastic ((Tocco et al, 2018) and reviewed in (Lele et al, 2018, Dickinson et al, 2022)). That is, deformed nuclear shapes in cells are not restored following the removal of cellular forces, suggesting that there is no storage of elastic energy in nuclear shape.…”

“…Unlike an oil drop in water where the surface tension arises from intermolecular attraction within each phase, surface tension in the nucleus arises due to resistance of the nuclear lamina to areal expansion. Because the lamina becomes tense due to an increase in nuclear pressure upon nuclear flattening in spread cells (Lele et al, 2018, Dickinson et al, 2022), nuclear rupture is expected to reduce the surface tension by releasing the nuclear pressure. This explains why lamin A/C -/- cells and lamin A/C -/- cells expressing GFP – Lamin A S22A/S392A similarly get entangled around microposts as both should have reduced surface tension.…”

“…Unlike an oil drop in water, where the surface tension arises from intermolecular attraction within each phase, surface tension in the nucleus arises due to resistance of the nuclear lamina to areal expansion. The source of tension in the lamina is likely the increase in nuclear pressure upon nuclear flattening in spread cells [7, 33] as well as the compression of the nucleus against the microposts. Lamin A/C is required to sustain this tension.…”

“…Thus, it is difficult to extrapolate the shortterm measurements to the long-timescale behavior. Also, we have previously shown that on the time scale of cell migration, nuclear deformations that occur during migration are not elastic and are primarily limited by the resistance of the lamina to areal expansion and the nuclear volume to compression ( [35, 42] , and reviewed in [7, 33] ). That is, on longer time scales, deformed nuclear shapes in cells are not restored following the removal of cellular forces because of any elastic energy stored in the nuclear shape.…”