Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation

Swift, Joe; Ivanovska, Irena L.; Buxboim, Amnon; Harada, Takamasa; Dingal, P.C. Dave P.; Pinter, Joel; Pajerowski, J. David; Spinler, Kyle R.; Shin, Jae Won; Tewari, Manorama; Rehfeldt, Florian; Speicher, David W.; Discher, Dennis E.

doi:10.1126/science.1240104

Cited by 1,661 publications

(2,330 citation statements)

References 123 publications

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“…1 c; refer to the Supporting Material for details). Recent work has shown that the nucleus is also viscoelastic, but the timescale of viscous relaxation is of the order of 1-300 s (14,15,19,20), which is an order of magnitude smaller than the time it takes the nucleus to pass through endothelial gaps/constrictions (3). Thus, the elastic properties we use here are the moduli after the viscous effects have relaxed.…”

Section: Model Formulationmentioning

confidence: 99%

“…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%

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

Cao

Moeendarbary

Isermann

et al. 2016

Biophysical Journal

116

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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Section: Model Formulationmentioning

confidence: 99%

Section: Ecm Stiffness and Gap Size Modulate Nuclear Transmigrationmentioning

confidence: 99%

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

Cao

Moeendarbary

Isermann

et al. 2016

Biophysical Journal

116

160

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“…From a structural perspective, the ECM has a fibrillar and viscoelastic character, and such biophysical features have been reported to have a significant influence on cell behavior [2][3][4] . Although the molecular pathways involved in cellular 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 mechanosensitivity are still open to investigation, it is well known that cells sense and respond to the stiffness of their environment by converting mechanical inputs into chemical outputs 5,6 . More recently, cell fate related to energy dissipation mediated by enzymatic ECM degradation has also been reported 7 .…”

Section: Introductionmentioning

confidence: 99%

Self-Organized ECM-Mimetic Model Based on an Amphiphilic Multiblock Silk-Elastin-Like Corecombinamer with a Concomitant Dual Physical Gelation Process

et al. 2014

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ABSTRACT. Although significant progress has been made in the area of injectable hydrogels for biomedical applications and model cell niches, further improvements are still needed, especially in terms of mechanical performance, stability and biomimicry of the native fibrillar architecture found in the extracellular matrix (ECM). This work focuses on the design and production of a silk-elastin-based injectable multiblock co-recombinamer that spontaneously forms a stable physical nanofibrillar hydrogel under physiological conditions. That differs from previously reported silk-elastin-like polymers on a major content and predominance of the elastin-like part, as well as a more complex structure and behavior of such part of the molecule, which is aimed to obtain well defined hydrogels.Rheological and DSC experiments showed that this system displays a coordinated and concomitant dual gelation mechanism. In a first stage, a rapid, thermally driven gelation of the co-recombinamer solution takes place once the system reaches body temperature due to the thermal responsiveness of the elastinlike (EL) parts and the amphiphilic multiblock design of the co-recombinamer. A bridged micellar 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 structure is the dominant microscopic feature of this stage, as demonstrated by AFM and TEM.Completion of the initial stage triggers the second, which comprises a stabilization, reinforcement, and microstructuring of the gel. FTIR analysis shows that these events involve the formation of β-sheets around the silk motifs. The emergence of such β-sheet structures leads to the spontaneous selforganization of the gel into the final fibrous structure. Despite the absence of biological cues, here we set the basis of the minimal structure that is able to display such a set of physical properties and undergo microscopic transformation from a solution to a fibrous hydrogel. The results point to the potential of this system as a basis for the development of injectable fibrillar biomaterial platforms towards a fully functional, biomimetic, artificial extracellular matrix and cell niches.

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“…Previous work showed that YAP functions in a mechanosensitive pathway and responds to increased tension, extracellular matrix stiffness, and cell spreading (Dupont et al, 2011;Rauskolb et al, 2014;Swift et al, 2013). These and other data suggest YAP may act in a positive feedback loop where tension stimulates YAP activation, and YAP responds by increasing tissue tension (Calvo et al, 2013).…”

mentioning

confidence: 88%

Crumbling under Pressure

Mason

Martin

2015

Developmental Cell

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Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation

Cited by 1,661 publications

References 123 publications

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

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

Self-Organized ECM-Mimetic Model Based on an Amphiphilic Multiblock Silk-Elastin-Like Corecombinamer with a Concomitant Dual Physical Gelation Process

Crumbling under Pressure

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