Nuclear lamin stiffness is a barrier to 3D-migration, but softness can limit survival

Harada, Takamasa; Swift, Joe; Irianto, Jerome; Shin, Jae Won; Spinler, Kyle R.; Athirasala, Avathamsa; Diegmiller, Rocky; Dingal, P.C. Dave P.; Ivanovska, Irena L.; Discher, Dennis E.

doi:10.1109/nebec.2014.6972810

Cited by 70 publications

(112 citation statements)

References 32 publications

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“…Recently, the differential expression of lamin A/C has been detected in cells subjected to different kinds of mechanical stimuli and has been shown to be involved in differential cellular functions. Harada et al (27) reported that differentially expressed lamin A/C can modulate cell migration and survival in human mesenchymal stem cells and two cancer cell lines. Swift et al (13) found that lamin A, but not lamin B, is changed by matrices of different stiffness and participates in the differentiation of mesenchymal stem cells induced by the stiffness of the culture matrix.…”

Section: Discussionmentioning

confidence: 99%

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Yao

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic stretch is an important inducer of vascular smooth muscle cell (VSMC) proliferation, which is crucial in vascular remodeling during hypertension. However, the molecular mechanism remains unclear. We studied the effects of emerin and lamin A/C, two important nuclear envelope proteins, on VSMC proliferation in hypertension and the underlying mechano-mechanisms. In common carotid artery of hypertensive rats in vivo and in cultured cells subjected to high (15%) cyclic stretch in vitro, VSMC proliferation was increased significantly, and the expression of emerin and lamin A/C was repressed compared with normotensive or normal (5%) cyclic stretch controls. Using targeted siRNA to mimic the repressed expression of emerin or lamin A/C induced by 15% stretch, we found that VSMC proliferation was enhanced under static and 5%-stretch conditions. Overexpression of emerin or lamin A/C reversed VSMC proliferation induced by 15% stretch. Hence, emerin and lamin A/C play critical roles in suppressing VSMC hyperproliferation induced by hyperstretch. ChIP-on-chip and MOTIF analyses showed that the DNAs binding with emerin contain three transcription factor motifs: CCNGGA, CCMGCC, and ABTTCCG; DNAs binding with lamin A/C contain the motifs CVGGAA, GCCGCYGC, and DAAGAAA. Protein/DNA array proved that altered emerin or lamin A/C expression modulated the activation of various transcription factors. Furthermore, accelerating local expression of emerin or lamin A/C reversed cell proliferation in the carotid artery of hypertensive rats in vivo. Our findings establish the pathogenetic role of emerin and lamin A/C repression in stretch-induced VSMC proliferation and suggest mechanobiological mechanism underlying this process that involves the sequencespecific binding of emerin and lamin A/C to specific transcription factor motifs.T he cyclic stretch caused by the rhythmical distention and relaxation of the arterial wall during the cardiac cycle is an important factor in the regulation of vascular modeling and remodeling (1, 2). There is growing evidence that mechanical cyclic stretch modulates the functions (e.g., apoptosis, proliferation, and migration) of vascular smooth muscle cells (VSMCs) in the media of the arterial wall (2) and that chronically elevated cyclic stretch stimulates VSMC functions to mediate vascular remodeling during hypertension (3, 4).It has been shown that there are various mechano-sensors in the vascular cell membrane, including lipids (5), glycocalyx (6), and proteins such as integrins (7), G proteins and G protein-coupled receptors (8), receptor tyrosine kinase (9), and Ca 2+ channel (10) and intercellular junction proteins (2, 11). In recent years, it has been suggested that nuclear envelope (NE) proteins, a hallmark of eukaryotic cells, participate in the mechano-transduction networks. Our previous proteomic analysis revealed that lamin A/C, one kind of NE protein, is mechano-responsive and may contribute to the shear stress-induced proliferation and migration of VSMCs (12). Recently, Swift et al. (13) ...

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Section: Discussionmentioning

confidence: 99%

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Yao

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…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.…”

Section: Ecm Stiffness and Gap Size Modulate Nuclear Transmigrationmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Cao

Moeendarbary

Isermann

et al. 2016

Biophysical Journal

113

160

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It is now evident that the cell nucleus undergoes dramatic shape changes during important cellular processes such as cell transmigration through extracellular matrix and endothelium. Recent experimental data suggest that during cell transmigration the deformability of the nucleus could be a limiting factor, and the morphological and structural alterations that the nucleus encounters can perturb genomic organization that in turn influences cellular behavior. Despite its importance, a biophysical model that connects the experimentally observed nuclear morphological changes to the underlying biophysical factors during transmigration through small constrictions is still lacking. Here, we developed a universal chemomechanical model that describes nuclear strains and shapes and predicts thresholds for the rupture of the nuclear envelope and for nuclear plastic deformation during transmigration through small constrictions. The model includes actin contraction and cytosolic back pressure that squeeze the nucleus through constrictions and overcome the mechanical resistance from deformation of the nucleus and the constrictions. The nucleus is treated as an elastic shell encompassing a poroelastic material representing the nuclear envelope and inner nucleoplasm, respectively. Tuning the chemomechanical parameters of different components such as cell contractility and nuclear and matrix stiffnesses, our model predicts the lower bounds of constriction size for successful transmigration. Furthermore, treating the chromatin as a plastic material, our model faithfully reproduced the experimentally observed irreversible nuclear deformations after transmigration in lamin-A/C-deficient cells, whereas the wild-type cells show much less plastic deformation. Along with making testable predictions, which are in accord with our experiments and existing literature, our work provides a realistic framework to assess the biophysical modulators of nuclear deformation during cell transmigration.

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“…In addition, modulations in cytoskeletal to nuclear links have been implicated in DNA damage and genome integrity (23,24). The maintenance of nuclear physical properties is also essential in cell migration during developmental programs (25) as well as in wound healing (26,27). Defects in nuclear morphology and its deformability have also been shown to be important in metastatic potential and cancer cell invasion (28).…”

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confidence: 99%

Nuclear deformability and telomere dynamics are regulated by cell geometric constraints

Makhija

Jokhun

Shivashankar

2015

Proc. Natl. Acad. Sci. U.S.A.

187

186

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Forces generated by the cytoskeleton can be transmitted to the nucleus and chromatin via physical links on the nuclear envelope and the lamin meshwork. Although the role of these active forces in modulating prestressed nuclear morphology has been well studied, the effect on nuclear and chromatin dynamics remains to be explored. To understand the regulation of nuclear deformability by these active forces, we created different cytoskeletal states in mouse fibroblasts using micropatterned substrates. We observed that constrained and isotropic cells, which lack long actin stress fibers, have more deformable nuclei than elongated and polarized cells. This nuclear deformability altered in response to actin, myosin, formin perturbations, or a transcriptional down-regulation of lamin A/C levels in the constrained and isotropic geometry. Furthermore, to probe the effect of active cytoskeletal forces on chromatin dynamics, we tracked the spatiotemporal dynamics of heterochromatin foci and telomeres. We observed increased dynamics and decreased correlation of the heterochromatin foci and telomere trajectories in constrained and isotropic cell geometry. The observed enhanced dynamics upon treatment with actin depolymerizing reagents in elongated and polarized geometry were regained once the reagent was washed off, suggesting an inherent structural memory in chromatin organization. We conclude that active forces from the cytoskeleton and rigidity from lamin A/C nucleoskeleton can together regulate nuclear and chromatin dynamics. Because chromatin remodeling is a necessary step in transcription control and its memory, genome integrity, and cellular deformability during migration, our results highlight the importance of cell geometric constraints as critical regulators in cell behavior. mechanotransduction | cell geometry | actomyosin contractility | chromatin dynamics | telomere dynamics P hysical properties of the nucleus, such as its morphology and deformability, have been associated with important cellular functions like gene expression, genome integrity, and cell behavior (1-3). The major cellular components that regulate these physical properties are the cytoskeleton to nuclear links and the nuclear lamina (4-8). Lineage-specific physical properties of the nucleus emerge during cellular differentiation; although stem cell nuclei are highly deformable (9, 10) and have a dynamic chromatin with hyperdynamic chromatin proteins (11), with differentiation, nuclei lose their deformability and become less deformable (12). The nucleus in a differentiated cell is physically coupled to the cytoskeleton via lamins and the linker of nucleoskeleton and cytoskeleton (LINC) complex, which comprises transmembrane Sad1p, UNC-84 (SUN) and Klarsicht, ANC-1, Syne Homology (KASH) domain proteins (13-18). Any perturbation to these components is linked to changes in nuclear morphology and deformability (19). Therefore, the meshwork of actin stress fibers and lamin A/C serves as a critical physical intermediate in the maintenance of nuclear func...

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Nuclear lamin stiffness is a barrier to 3D-migration, but softness can limit survival

Abstract: Abbreviations used in this paper: MMP, matrix metalloproteinase; MS, mass spectrometry; MSC, mesenchymal stem cell; PMN, polymorphonuclear leukocyte; siLMNA, short interfering LMNA.

Cited by 70 publications

References 32 publications

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application

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

Nuclear deformability and telomere dynamics are regulated by cell geometric constraints

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