The Nucleus Bypasses Obstacles by Deforming Like a Drop with Surface Tension Mediated by Lamin A/C

Abstract

Migrating cells must deform their stiff cell nucleus to move through pores and fibers in tissue. Lamin A/C is known to hinder cell migration by limiting nuclear deformation and passage through confining channels, but its role in nuclear deformation and passage through fibrous environments is less clear. Cell and nuclear migration through discrete, closely spaced, slender obstacles which mimic the mechanical properties of collagen fibers are studied. Nuclei bypass slender obstacles while preserving their overall morphology by deforming around them with deep local invaginations of little resisting force. The obstacles do not impede the nuclear trajectory and do not cause rupture of the nuclear envelope. Nuclei likewise deform around single collagen fibers in cells migrating in 3D collagen gels. In contrast to its limiting role in nuclear passage through confining channels, lamin A/C facilitates nuclear deformation and passage through fibrous environments; nuclei in lamin‐null ( Lmna −/− ) cells lose their overall morphology and become entangled on the obstacles. Analogous to surface tension‐mediated deformation of a liquid drop, lamin A/C imparts a surface tension on the nucleus that allows nuclear invaginations with little mechanical resistance, preventing nuclear entanglement and allowing nuclear passage through fibrous environments.

A predictive unifying explanation for nuclear shapes based on a simple geometric principle

“…Here we calculated remarkably similar nuclear shapes by translating a 1-micron diameter micropost toward the nuclear center while recursively calculating the deformed equilibrium nuclear shape. We did not otherwise model the interaction between the micropost and cell, consistent with the experimental observation that the micropost was fully engulfed in the cytoplasm [42]. The calculated nuclear shapes for 𝜀 = 40-60% closely resemble the experimentally observed nuclear shapes (Figure 7).…”

“…Lastly, we test the ability of the geometric model to explain the overall nuclear shapes when the nucleus develops deep nuclear invaginations, as we have recently reported in nuclei impinging against microposts [42]. In these experiments, nuclei in migrating cells contact the microposts, creating invaginations into the nuclear lamina (Figure 7), similar to the deformation of a liquid drop with surface tension.…”

“…Our results predict that nuclear pressure and lamina surface tension should arise in cell geometries that fully unfold the lamina excess area (which is the case for most mammalian cells in culture). Nuclear pressure and resulting lamina tension explain the source and magnitude of forces exerted on microposts forming deep invaginations in nuclei [47].The prediction of tension in the lamina upon unfolding is also consistent with the observation that mechanosensitive yesassociated protein (YAP) import to the nucleus correlates with nuclear unwrinkling in cells in 2D culture [37], and the rupture of nuclei during stretching of the lamina during cell migration through confining spaces [48]. As YAP translocation regulates gene expression, while deformation and rupture can promote DNA damage and tumorigenesis, the mechanical state of the nuclear lamina predicted by the model is likely to be important in both healthy and diseased cells.…”

“…Thus, the bending energy of the lamina, even in the regions of highest curvature, should be negligible, being 2-3 orders of magnitude smaller than the calculated values of lamina surface tension. Furthermore, the nuclear lamina commonly exhibits folds and wrinkles on time scales of tens of minutes or longer during cell spreading before a limiting shape with a smoothed lamina is reached [44]. Thus, it is unlikely that resistance to bending of the lamina or the other envelope components plays a significant role in driving nuclear shape changes, at least on the longer time and length scales considered here.…”

“…The lamina can protect the nucleus from extreme deformations, while otherwise permitting mechanical compliance due to its excess area. For example, nuclear pressure and the resulting lamina tension explain the source and magnitude of forces exerted on microposts which indent nuclei [44] in migrating cells (c.f. Figure 8).…”