Nuclear Deformability Constitutes a Rate-Limiting Step During Cell Migration in 3-D Environments

Abstract

Cell motility plays a critical role in many physiological and pathological settings, ranging from wound healing to cancer metastasis. While cell migration on 2-dimensional (2-D) substrates has been studied for decades, the physical challenges cells face when moving in 3-D environments are only now emerging. In particular, the cell nucleus, which occupies a large fraction of the cell volume and is normally substantially stiffer than the surrounding cytoplasm, may impose a major obstacle when cells encounter narrow constrictions in the interstitial space, the extracellular matrix, or small capillaries. Using novel microfluidic devices that allow observation of cells moving through precisely defined geometries at high spatial and temporal resolution, we determined nuclear deformability as a critical factor in the cells’ ability to pass through constrictions smaller than the size of the nucleus. Furthermore, we found that cells with reduced levels of the nuclear envelope proteins lamins A/C, which are the main determinants of nuclear stiffness, passed significantly faster through narrow constrictions during active migration and passive perfusion. Given recent reports that many human cancers have altered lamin expression, our findings suggest a novel biophysical mechanism by which changes in nuclear structure and composition may promote cancer cell invasion and metastasis.

A Chemomechanical Model for Nuclear Morphology and Stresses during Cell Transendothelial Migration

“…We also quantitatively investigated the influence of transmigration on cell nuclei, including nuclear shapes, chromatin deformations, and NE deformations. Our results predict nuclear shape profiles that closely agree with both our experimental observations and previously published data (8,9,13,25). Furthermore, investigating the nuclear profiles and the distribution of strain within the nucleus, we conclude that the primary driving forces (particularly for transmigration through small gaps) are those that pull the nucleus from the front.…”

“…4 a). This hourglass shape has been observed in various cell migration experiments (8,13,25,39). Interestingly, our model predicts that E 1 and E 2 are mostly tensile and compressive, respectively, consistent with the experimental patterns of strain maps derived based on the triangulation between the individual, naturally present dense chromatin foci (Fig.…”

“…It has been shown that the levels of the NE proteins lamin A and C (lamin A/C) determine the stiffness of the nucleus (20,(31)(32)(33), and that lower levels of lamin A/C facilitate cell migration through tight spaces (8,10,34). We studied the influence of lamin A/C on transmigration by varying the modulus of the NE in our model (Fig.…”

“…During these processes, the cell size, rheological properties and the geometric parameters associated with the extracellular environment dictate the maximal rate at which the cell can transmigrate and change its shape (6,7). The nucleus, being the largest and the stiffest organelle within the cell, is a physical constraint to migration and may be a rate-limiting factor for cellular deformations during cell migration through three-dimensional (3D) constrictions that are smaller or comparable to the nuclear cross section (8)(9)(10). On the other hand, since the nucleus houses the genetic machinery of the cell, changes in the nuclear morphology and positioning within the cytoplasm during migration can influence the phenotypic profile of the cell (5,11).…”

Constricted cell migration causes nuclear lamina damage, DNA breaks, and squeeze-out of repair factors

“…Similar studies of others likewise showed enhanced migration in vitro 3,19 . The nuclear lamina has likely evolved to protect the genome and enhance cell viability.…”