COMMENTARY - Journal of Cell Science · 2014. 7. 8. · the concentration of ECM components and...

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COMMENTARY

The nuclear lamina is mechano-responsive to ECM elasticity inmature tissue

Joe Swift and Dennis E. Discher*

ABSTRACT

How cells respond to physical cues in order to meet and withstand

the physical demands of their immediate surroundings has been of

great interest for many years, with current research efforts focused

on mechanisms that transduce signals into gene expression.

Pathways that mechano-regulate the entry of transcription factors

into the cell nucleus are emerging, and our most recent studies

show that the mechanical properties of the nucleus itself are actively

controlled in response to the elasticity of the extracellular matrix

(ECM) in both mature and developing tissue. In this Commentary,

we review the mechano-responsive properties of nuclei as

determined by the intermediate filament lamin proteins that line

the inside of the nuclear envelope and that also impact upon

transcription factor entry and broader epigenetic mechanisms.

We summarize the signaling pathways that regulate lamin levels

and cell-fate decisions in response to a combination of ECM

mechanics and molecular cues. We will also discuss recent work

that highlights the importance of nuclear mechanics in niche

anchorage and cell motility during development, hematopoietic

differentiation and cancer metastasis, as well as emphasizing a role

for nuclear mechanics in protecting chromatin from stress-induced

damage.

KEY WORDS: Cell mechanics, Mechanotransduction, Extra-cellular

matrix, Nucleus, Nucleoskeleton, Proteostasis

IntroductionEvolution has likely driven our tissues and organs to fulfill their

roles with optimal efficiency and, of course, viability. Mature

tissues need to be particularly resistant to the mechanical

demands of an active life. Our bones, cartilage, skeletal muscleand heart tissues are stiff, making them robust and resistant to

routine physical exertion, such as walking or running, during

which they are subjected to high-frequency shocks, stresses and

strains. With every heartbeat, the left ventricular wall experiencesa 20% radial strain (Aletras et al., 1999), and local strains of

,20% also occur in the cartilage of knee joints with every step(Guilak et al., 1995). Tissue-level deformations might even be

amplified within cells and their nuclei (Henderson et al., 2013).Our softer tissues have less need for robustness because their

function does not require them to bear load. Furthermore, some of

our softest tissues, such as brain and marrow, are protected fromshocks and stresses by our bones. Nonetheless, when soft tissues

are subjected to impact, such as during a collision of heads in

American football or rugby, occurrences of rapid straining cancause lasting damage (Viano et al., 2005).

We have recently sought to characterize the composition ofcells and extra-cellular matrix (ECM) in tissues of increasingstiffness, and by implication, in tissues that are subjected to thegreatest stress (Swift et al., 2013b). A close correlation between

the concentration of ECM components and bulk tissue elasticitywas discovered for mouse tissues (Swift et al., 2013b). Moresurprisingly, we also discovered a systematic scaling between

tissue elasticity and the concentration of lamins in thenucleoskeleton that was partially re-capitulated in cultured cellsystems (Swift et al., 2013b). Corresponding changes to nuclear

mechanical properties associated with this tuning of laminacomposition suggest that this response might act to protect thechromatin cargo of the nucleus from shocks that are transmitted

through the surroundings, across the cytoskeleton and into thenucleus. An active regulation of cell or ECM composition inresponse to the environment implies feedback into pathways ofprotein turnover and remodeling, or control of the rate of new

protein production. Responsive matching of mechanical propertiesto physical demands has classically been described as a‘mechanostat’ in the context of bone regulation (Frost, 1987), but

a recent explosion in mechanobiological studies has uncovered ahost of other mechanically sensitive cellular phenomena, includingcontraction (Discher et al., 2005), migration (Hadjipanayi et al.,

2009b; Winer et al., 2009; Raab et al., 2012), proliferation(Hadjipanayi et al., 2009a; Klein et al., 2009; Lo et al., 2000),differentiation (Engler et al., 2004; Engler et al., 2006) and

apoptosis (Wang et al., 2000). However, despite great recentprogress, questions of how mechanical signals are transduced intospecific transcriptional or regulatory pathways continue tochallenge the field.

The lamina is a network structure formed from intermediatefilament lamin proteins, and it lies just inside the nuclear

envelope and interacts with both chromatin and the cytoskeleton(Fig. 1A). In the somatic cells of humans, mice and mostvertebrates, the main forms of lamin protein are expressed from

three genes: lamin-A and lamin-C are alternatively splicedproducts of the LMNA gene, and they are collectively referredto as ‘A-type’ lamins; lamin-B1 and lamin-B2 are encoded by the

LMNB1 and LMNB2 genes, respectively, and are known as ‘B-type’ lamins. The lamins share structural features and, indeed,have some similarity in amino acid sequence, but they differ intheir post-translational modification, with B-type lamins

permanently appended by a farnesyl group that is cleaved frommature lamin-A (reviewed, for example, by Dechat et al., 2010;Ho and Lammerding, 2012). Like other intermediate filament

proteins, such as keratin and vimentin, the lamins form coiled-coil parallel dimers that assemble into higher-order filamentousstructures that fulfill important structural roles (Herrmann et al.,

2009).

Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia,PA 19104, USA.

*Author for correspondence ([email protected])

� 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 3005–3015 doi:10.1242/jcs.149203

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Micropipetteaspiration

Embryonicheart

Log (micro-stiffness)

Bone

Brain

Marrow

Fat MuscleLo

g (A

-type

:B-ty

pe la

min

) A-type lamin dominant

B-type lamin dominant

Lung

Kidney

Heart

Liver

Cartilage

Log

(type

I co

llage

n)

Log (micro-stiffness)

High collagen stiff tissue

Muscle

Heart

Lung

Brain

Liver

Bone

Cartilage

Kidney

Fat

Embryonic disc

Embryo age (days)

Log

(mic

ro-s

tiffn

ess)

Adult range

Adult range

Heart

Brain

Embryo age (days)

Log

(type

I co

llage

n)

Heart

Brain

Pluripotent Fibroblast

Rel

ativ

e nu

clea

r stif

fnes

s

HighA-typelamin

LowA-typelamin

AdultTime in culture (days)

Nuclear envelope

SUN proteinsNesprins

Cytoskeletalproteins

LINCcomplex

ChromatinA-type laminB-type lamin

Nuclear lamina

Chromatin

ChromatinNuclear poresF-actin

Microtubules

Nucleus

Intermediate filaments

Lamin-A

Lamin-C

Lamin proteins

Lamin-B1

Lamin-B2

Ig-domain

LMNA

LMNB1

LMNB2

Coiled-coil domains

Common region

Very lowA-type lamin

Stem celldifferentiation

Very low A-type lamin

B Lamin-A scales with the collagen-dependent stiffness of mature tissues

C Tissue stiffens in development and so does the nucleus

A A- and B-type lamins assemble between the nuclear envelope and chromatin

Fig. 1. Relationship between the ECM and lamin in mature tissue and during development. (A) A-type and B-type lamins (red and blue, respectively) formjuxtaposed networks on the inside of the nuclear envelope; they are effectively located at an interface between chromatin and the cytoskeleton, the latter ofwhich is attached to the lamina through the LINC complex (shown in the magnified view). The A-type lamins, lamin-A and lamin-C, are alternativespliceoform products of the LMNA gene; the B-type lamins, lamin-B1 and lamin-B2, are protein products of LMNB1 and LMNB2, respectively (adapted fromBuxboim et al., 2010a, originally published in The Journal of Cell Science). (B) Left: the quantity of type I collagen present in tissues is proportional to tissuemicro-elasticity (Swift et al., 2013b). As collagen is one of the most prevalent proteins in the body, it is, perhaps, expected that it defines mechanical properties.Right: the ratio of A-type lamin to B-type lamin in the nuclear lamina is proportional to tissue microelasticity. The lamina contains predominantly A-type laminsin stiff tissue, whereas B-type lamins are prevalent in the nuclear lamina in soft tissue (Swift et al., 2013b). (C) Left: observations made in adult tissue areconsistent with results from the developing chick; the embryonic disc was initially soft, but divergent tissues either remained soft (e.g. brain, blue) orbecame increasingly stiff (e.g. heart, red). Inset: developing chick hearts were probed by micropipette aspiration to determine micro-elasticity. Middle: tissuestiffening during development is accompanied by increased levels of collagen and A-type lamins (Lehner et al., 1987; Majkut et al., 2013). Right: embryonic stemcells initially express negligible quantities of A-type lamin proteins, but these levels increase as the nucleus stiffens during lineage commitment (Pajerowskiet al., 2007).

COMMENTARY Journal of Cell Science (2014) 127, 3005–3015 doi:10.1242/jcs.149203

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This Commentary aims to summarize recent efforts tocharacterize the proteins that vary systematically with tissue

stiffness. The effects of the composition of the lamina on nuclearmechanical properties will be elaborated in detail, and we willconsider the functions of the lamina in transducing mechanicalsignals from the ECM and the surroundings of the cell into

cellular responses, both in terms of the active regulation of thelamina itself and its broader role in linking mechanotransductionpathways. Although we focus on a primarily protective function

of nuclear lamin, there are additional regulatory consequences ofpossessing such a stiff and bulky organelle as the nucleus, and wewill summarize recent evidence that such properties limit the

freedom of cells to move through tissue. The proximity of thelamina to heterochromatin within the nucleus has led it to bewidely associated with epigenetic regulation (e.g. Kim et al.,

2011; Meuleman et al., 2013). This Commentary seeks tohighlight the pervasive influence of the mechanical role of thelamina and hence proposes that lamin acts as both the guardianand the gatekeeper of chromatin.

Scaling of ECM and lamina components in mature anddeveloping tissueCollagens and other protein constituents of the ECM are the mostprevalent proteins in our bodies, largely determining themechanical properties of tissue. Collagens are found at higher

levels in stiff mature tissues where, consistent with an expectationfor proteins to behave as ‘biological polymers’ (Gardel et al.,2004), their increased concentration is the basis of tissue elasticity

(Fig. 1B, left panel). By using quantitative label-free massspectrometry for proteomic profiling (Swift et al., 2013a), wehave shown that collagens and other ECM-associated proteinsscale with tissue elasticity (Swift et al., 2013b). Mass

spectrometry was also used to quantify ,100 of the mostabundant proteins in the cytoskeleton and nucleus, and we foundthat the elasticity of bulk tissue is strongly correlated with the

composition of the nuclear lamina in terms of its content of A-type and B-type lamins (Fig. 1B, right panel). Although primarilycharacterized by the ratio between these two main families of

lamins, the compositional scaling is dominated by a 30-foldincrease in the concentration of A-type lamin from brain to bone.Although our recent observations are broadly in agreement withan extensive literature on lamin quantification (e.g. Broers et al.,

1997; Cance et al., 1992; Krohne et al., 1981; Röber et al., 1990),they provide a new perspective on systematic variations acrossmany tissues.

The relationship between tissue stiffness and ECM duringdevelopment has also been determined (Majkut et al., 2013);micropipette aspiration of embryonic chick tissue showed that the

homogeneous embryonic disk is initially very soft, withproteomic profiles indicating correspondingly low levels ofcollagen (Fig. 1C, left and middle panels). However, the

properties of different tissues diverge during development, withthe brain remaining soft, whereas the heart stiffens as ECMproteins are deposited (Majkut et al., 2013). Cells in stiffeningtissues, such as the heart, are also likely to have correspondingly

higher levels of lamin-A and lamin-C (Lehner et al., 1987).Nuclei in embryonic stem cells have, indeed, been shown to bevery soft and to have low levels of lamin-A and lamin-C

(Eckersley-Maslin et al., 2013; Pajerowski et al., 2007). As thesecells commit to a lineage-specific fate, the levels of these laminsincrease, and the nucleus becomes correspondingly stiffer

(Fig. 1C, right panel).

Importantly, despite an apparent role in reinforcing thedecisions of animal cell fate (in conjunction with ECM

elasticity) (Swift et al., 2013b), lamin-A and lamin-C are notessential to development, because knockout mice that lack A-typelamins still form all tissues (Sullivan et al., 1999). Likewise,lamin-B knockout mice survive embryogenesis (Kim et al.,

2011), and embryonic stem cells can be cultured anddifferentiated without having any lamins (Kim et al., 2013).The most crucial role of lamin might therefore be to fine-tune the

properties and regulation of maturing tissues in higher organisms,and its absence can perhaps be compensated for duringdevelopment. However, we note that the distinction here might

be blurred; there is still a need to regulate and maintain nuclearstructure during some stages of development, such as during cellmigration, and the processes of trafficking and differentiation

continue throughout the lifespan. Nonetheless, the fact thatlamins are not absolutely essential for cell viability is consistentwith the current notion that lamins are not expressed in yeast andplants (Dittmer and Misteli, 2011), despite the latter possessing

genomes that are larger and more complex than those of animals.The hard cell walls of these organisms likely protect thechromatin in a manner that is not possible for animal cells with

soft cell membranes.

The influence of lamina composition on the mechanicalproperties of the nucleusMicropipette aspiration experiments have enabled the detailedstudy of the mechanical properties of the nucleus, which can be

investigated by measuring the rate of deformation under pressure(Fig. 2A,B; Dahl et al., 2005; Pajerowski et al., 2007). Byexamining nuclei with different lamina compositions, it is thuspossible to approximate the characteristic contributions of A-type

and B-type lamins to nuclear properties (Fig. 2C; Harada et al.,2014; Shin et al., 2013; Swift et al., 2013b). The nuclearmechanical response has been characterized as a combination of

elastic (spring-like) and viscous (liquid-like, flowing) properties,with B-type lamins contributing primarily to the elastic responseand A-type lamins contributing to the viscosity (Harada et al.,

2014; Shin et al., 2013; Swift et al., 2013b). Thus, the differencebetween a nucleus in which the lamina is stoichiometricallydominated by A-type versus B-type lamins might be akin tocomparing a balloon filled with honey to one filled with water.

The importance of A-type lamins in maintaining nuclearstructural integrity and cell viability has been appreciated formany years (e.g. Broers et al., 2004; Lammerding et al., 2006),

and the influence of A-type lamins on nuclear viscosity has beenmore recently demonstrated in studies where nuclei are deformedduring migration through microfluidic circuits (Rowat et al.,

2013) or transwell pores (discussed later; Harada et al., 2014).Laminopathies are a family of diseases that are caused by

truncations or single amino acid substitutions in A-type lamins

(reviewed, for example, by Butin-Israeli et al., 2012; Davidsonand Lammerding, 2014; Isermann and Lammerding, 2013;Worman, 2012). These disorders include muscular dystrophies(Bonne et al., 1999), cardiomyopathies (Fatkin et al., 1999),

lipodystrophies (Hegele et al., 2000; Shackleton et al., 2000;Speckman et al., 2000) and premature ageing (termed ‘progeria’;Merideth et al., 2008). Indeed, one of the confounding aspects of

lamin-related disease is the mechanism by which such a widelyexpressed protein can cause tissue-specific symptoms. Althoughmuch further work is needed to resolve this question, it is broadly

true that laminopathies cause defects in tissues where A-type


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lamins are the dominant nuclear lamin (i.e. bone, heart, muscleand fat). However, there are exceptions – Charcot-Marie-Toothdisorder affects the nervous system (De Sandre-Giovannoli et al.,2002). Mouse models of A-type lamin knockout display defects

in muscle and connective tissue and typically die from heartfailure several weeks after birth (Jahn et al., 2012; Kubben et al.,2011; Sullivan et al., 1999). Despite the apparently constitutive

expression of B-type lamins, mouse models with lamin-B1 andlamin-B2 ablation progress through embryogenesis, with theireventual death being due to defects in brain development

(Coffinier et al., 2011; Kim et al., 2011).

Mechanisms of lamin regulationEarlier discussion has posited that lamins are closely regulated to

match the mechanical properties of the nucleus with the physicaldemands of the tissue. In addition to being determined by theepigenetic programming required to make a given tissue or organ,

it is also important to note that protein levels vary in response tofeedback from their surroundings. Even within bulk tissues,mechanical loading can cause inhomogeneous straining (for

example in human articular cartilage, meniscus and ligaments;Chan and Neu, 2012), making it beneficial to have mechanisms oflamin regulation that act at the local level of individual cells.

The many mechanisms by which the levels of lamin-A andlamin-C can be regulated are summarized in Fig. 3A. We haveshown that the transcript and protein levels of A-type lamins arehighly correlated in tissue (Swift et al., 2013b), a finding that is

suggestive of a tight regulatory feedback. A recent study of theproteome and transcriptome in mouse fibroblasts showed thatthere are around 107 copies of A-type lamin proteins per cell –

accounting for about 0.7% of cellular protein mass – and around200 copies of the LMNA transcript. Half-life in the cell is reportedto be ,4 days for the protein and ,20 hours for the mRNA, bothslightly higher than the cellular average for all proteins andtranscripts (Schwanhäusser et al., 2011). Measurements made onproteins in a human lung cancer cell line showed the half-life ofA-type lamin to be ,12 hours, roughly in the middle of the spanof protein half-lives recorded in the study (Eden et al., 2011).DNA methylation is an epigenetic mechanism by which gene

activity can be regulated, but it was discounted as the foremostmeans of controlling LMNA levels – no consistent changes wereobserved in the methylation of the LMNA promoter either in arange of cell lines known to express different levels of A-type

lamin protein (Swift et al., 2013b) or in tissues from patients withlaminopathic disorders (Cortese et al., 2007). LMNA transcriptionhas been reported to be controlled by transcription factors of the

retinoic-acid receptor family (RAR and RXR family proteins;Okumura et al., 2004a; Okumura et al., 2004b; Olins et al., 2001;Shin et al., 2013; Swift et al., 2013b), with the resulting mRNA

alternatively spliced to give the lamin-A and truncated lamin-Cforms. Soft tissue generally preferentially expresses the lamin-Cspliceoform (Swift et al., 2013b), and, in brain, the micro-RNAMIR-9 specifically targets and deactivates the mRNA of the

lamin-A spliceoform (Jung et al., 2012; Jung et al., 2013). Littleis currently understood about different functional roles of lamin-A and lamin-C, although differences in both physical properties,

such as mobility (Broers et al., 2005), and lamina assembly (Kolbet al., 2011; Pugh et al., 1997) have been reported.

Stress-responsive regulation of lamin – ‘use it or lose it’To better understand how lamin proteins are actively regulated inresponse to stress, mesenchymal stem cells (MSCs) were cultured

on type-I-collagen-coated polyacrylamide hydrogels withstiffnesses that were set to mimic the ECM of either brain(0.3 kPa) or pre-calcified bone (40 kPa) (Buxboim et al., 2010b;Swift et al., 2013b). Images of the cultured MSCs showed

that the nuclear envelopes of cells on soft substrate arewrinkled and relaxed, whereas, on stiff substrate, the nuclei areflattened by stress fibers and appear taut and smooth (Fig. 3B,

left panel). Accompanying proteomic analyses revealed that thenative fold of A-type lamin is maintained on stiff substrate(specifically, that of the globular Ig-like domain), but that the

total quantity of A-type lamin protein is upregulated.Furthermore, the extent of phosphorylation at four sites isdecreased on stiff substrate. Phosphorylation is recognized as akey mechanism for modulating the solubility, conformation and

organization of intermediate filament proteins (Omary et al.,2006), and indeed, lamins are highly phosphorylated during

Lamin-A increases nuclear viscosity

L

ΔP

Lamin-B(elastic)

Lamin-A(viscous)

ViscosityElasticity

Nuc

lear

com

plia

nce

Time (seconds)

Low LMNA

MediumLMNA

High LMNA

Soft

Stiff

Nucleus (GFP-lamin-A)

Micropipette

Tim

e

Deformationresponse time

A CB

Fig. 2. The mechanical role of lamin in the nucleus. (A) Deformations applied by micropipette aspiration were used to quantify nuclear compliance(effectively a measure of ‘softness’, the inverse of stiffness) in a range of nuclei with experimentally altered lamina compositions (achieved, for example, byoverexpressing a GFP–lamin-A fusion construct). Compliance can be calculated over a range of deformation timescales as a function of the micropipettediameter, the extent of deformation (L) and the applied pressure (DP). (B) When a constant deforming pressure was delivered by micropipette over timescales onthe order of seconds, nuclei with low expression of lamin-A (LMNA) were found to be more compliant than those with high expression of lamin-A. (C) Themechanical properties of the lamina can be considered as a combination of elastic (spring-like) and viscous (flowing) properties, which together define the‘deformation response time’, the timescale over which the nuclear shape deforms under force. Nuclei with greater quantities of A-type lamins relative to B-typelamins were found to deform more slowly under stress (Swift et al., 2013b).


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normal mitosis, driving the disassembly of the lamina inpreparation for chromosomal separation (Gerace and Blobel,

1980; Heald and McKeon, 1990). Thus, the response we observeto substrate-induced stress is the converse of this process, withdecreased phosphorylation acting to decrease A-type lamin

solubility and so strengthening the lamina. On soft substrate, A-type lamins are more extensively phosphorylated, more mobileand so, we hypothesize, more susceptible to turnover (as observedfollowing Akt-mediated phosphorylation of S404 in prelamin-A

(Bertacchini et al., 2013). These observations hence point to a‘use it or lose it’ dynamic, whereby non-essential A-type lamin is

eventually degraded. The level of A-type lamins has beenreported to drive the translocation of the lamin-promoting

transcription factor retinoic acid receptor c (RARG) to thenucleus, pointing to a feedback mechanism by which laminprotein promotes its own transcription (see gene circuit in Swift

et al., 2013b).There are a number of cases in the literature where cell mechanics

are regulated by phosphorylation or, by contrast, where externalstresses drive changes in phosphorylation state. As an example of

the former, changes in the phosphorylation of microtubuleassociated proteins (MAPs) affect the assembly of microtubules

Cytoplasm

Alternativesplicing

miRNA Translation

Solubility-regulatedby phosphorylation Degradation

Nuclear laminaAssembly (under stress)

Disassembly (relaxed)

LMNA

Stress-inducedprotein unfolding

Stress-inducedmembrane crackingTranscription factor andsmall molecule import

LMNA promoter

Nucleoplasmicphospho-lamin

LMNCLamin-ALamin-CTranscription

Chromatin interactionwith lamina

Tension

A-typelamin

B-typelamin

Kinase X

LMNA

Soft substrate relaxed nuclei

Stiff substrate tense nuclei

Ig domain

TailCoiled coil

Tension

Coiled-coil filaments Proteases

Retinoic-acid-binding factors

Nucleus

Wrinkled lamina Smooth lamina

Turnover ofunstressedfilaments

A Regulation of A-type lamin protein feeds back on transcription

B Tension-dependent regulation of protein levels

Time

Probe tips used to apply strain

Fig. 3. Protein regulation as a function of stress. (A) Schematic showing the factors that can regulate the levels of A-type lamin in the cell. LMNAtranscription is promoted by retinoic-acid-binding factors (Okumura et al., 2004a; Olins et al., 2001). The transcript (gray) is alternatively spliced to give rise tolamin-A and lamin-C forms. In some tissues, such as brain, the lamin-A form is suppressed through miRNA (Jung et al., 2012). Mature lamin-A (following post-translational processing) and lamin-C (both shown in red) assemble into the nuclear lamina, although some protein remains mobile in the nucleoplasm (Shimiet al., 2008). Phosphorylation leads to increased solubility, and might precede enzymatic protein turnover. Further stress-dependent pathways have beenreported; stress on the nucleus causes unfolding of the Ig-domain of A-type lamin, and phosphorylation is suppressed under tension (Swift et al., 2013b).Laminopathic nuclei have been shown to have transient membrane defects that allow ingress of transcription factors (De Vos et al., 2011). (B) Left: the nuclei ofMSCs cultured on soft substrate are wrinkled, whereas those in cells on stiff substrate have a smooth stretched appearance, suggestive of greater tension.We have shown that A-type lamin is less phosphorylated under tension – we hypothesize that this might be because interaction with kinases is altered by stress-induced changes in the organization of lamin protein filaments (Swift et al., 2013b). A lower level of phosphorylation reduces the solubility and mobility of laminand thus drives a ‘stress-strengthening’ of the lamina (Swift et al., 2013b). Right: collagen fibrils under tension have been shown to be less susceptible toenzymatic digestion; when a film of fibrillar collagen is subjected to localized stretching, subsequent treatment with a matrix metalloproteinase degrades thecollagen but the fibrils that are under tension remain intact (Flynn et al., 2010). This experiment is another example of multimeric coiled-coil protein assemblybeing enzymatically regulated when subjected to stress, suggesting some generality for the mechanism. Arrowheads indicate the direction of tension.


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that have important structural roles in the cytoskeleton (Mateniaand Mandelkow, 2009). Instances of the second case include both

the extension-dependent phosphorylation of the Cas substratedomain protein, p130Cas (also known as BCAR1), whichtransduces mechanical stretching into biochemical signaling(Sawada et al., 2006), and the phosphorylation of non-muscle

myosin-IIa (encoded by MYH9), which is inversely related tosubstrate stiffness and acts to regulate cell contractility (Raab et al.,2012). Recent work has shown that the nuclear envelope protein

emerin is phosphorylated in response to cell contractility, whichconsequently influences nuclear rigidity and, potentially, the wayin which emerin interacts with other nuclear proteins such

as lamin-A and lamin-C (Guilluy et al., 2014). Furthermore,phosphorylation events could be key to driving the transport ofproteins such as transcription factors to the nucleus, where they

have crucial regulatory roles (Jans and Hübner, 1996).The concept of ‘stress strengthening’ is also found in other

biological systems; stretched type I collagen fibrils were found tobe less susceptible to enzymatic degradation (Fig. 3B, right

panel; Flynn et al., 2010). Although the mode of enzymatic actiondiffers between A-type lamin and type I collagen, both areexamples of polymeric structural proteins that are protected from

degradation pathways when they are under tension. Theseparallels should also serve as reminders that, although thisreview is primarily focused on stress response within the cell, the

ECM in living tissue is also being continuously remodeled inresponse to extracellular cues (Xu et al., 2009).

Mechanotransduction to the nucleus – downstream of ECMand laminLamin is a key component in a system of protein linkages thatallows the transmission of signals from the surroundings of a cell

into the transcriptional machinery of its nucleus (Fig. 1A;discussed in recent reviews, e.g. Gundersen and Worman, 2013;Rothballer and Kutay, 2013; Simon and Wilson, 2011; Sosa et al.,

2013). Cell–cell interactions link to the cytoskeleton throughtight junctions and adherens junctions that tether to actin, andthrough desmosome complexes that interact with cytoplasmic

intermediate filaments, such as keratin (Jamora and Fuchs, 2002).Cell–ECM interactions are mediated by integrins and focaladhesion complexes that bind to cytoplasmic actin (Puklin-Faucher and Sheetz, 2009; Watt and Huck, 2013). The

appropriately named LINC complex (linker of nucleoskeletonand cytoskeleton) acts as an intermediary between cytoplasmicand nuclear structural proteins; F-actin binds to the nuclear

envelope components nesprin-1 and nesprin-2, and intermediatefilaments bind to the desmosome protein plectin, which, in turn,binds to nesprin-3. Nesprins can also interact with kinesin and

dynein complexes to tether to the microtubule network; nesprinsbind to the SUN-domain-containing family of inner nuclearmembrane proteins and these, in turn, bind to the lamina on the

inside of the nuclear envelope.Lamins engage in extensive protein–protein interactions within

the nucleus (Wilson and Berk, 2010; Wilson and Foisner, 2010),as emphasized by Wilson and Berk in their review: ‘‘almost all

characterized [inner nuclear membrane] proteins bind to A- or B-type lamins (or both) directly’’. These interactions includebinding to structural proteins, like actin (Simon et al., 2010),

and binding to a range of proteins that interact with the nuclearmembrane, including emerin, barrier-to-autointegration factor(BANF; Montes de Oca et al., 2009), lamina-associated

polypeptide 2 (LAP2, also known as ERBB2IP) and lamin-B

receptor (LBR; Solovei et al., 2013). Of these, emerin hasattracted considerable recent interest for its role in mediating

changes in the stiffness of isolated nuclei in response to tensionapplied to nesprin-1 (Guilluy et al., 2014), and its role inmechanosensing through its effect on the translocation of thetranscription factor MKL1 (Ho et al., 2013). Furthermore, some

transcription factors, such as Oct-1, interact with the laminadirectly (Malhas et al., 2009). Many lamin-binding proteins alsointeract with chromatin, particularly in its silenced heterochromatic

form (Wagner and Krohne, 2007), and indeed, the lamins havebeen shown to bind to DNA directly (Ludérus et al., 1992;Shoeman and Traub, 1990; Stierlé et al., 2003). This chain of

interactions thus completes a continuous physical linkage throughwhich deformations can be transmitted from the cell exterior tochromatin (Maniotis et al., 1997). What is missing from this

picture, however, is an understanding of the mechanism by whichblunt inputs – forces and perturbations acting without microscopiccoherence – can be converted from mechanical to biochemicalsignals to activate individual genes at precise spatial locations

within the nucleus. Perhaps specificity can be delivered throughchanges in binding, local concentration, conformation andmodification of cofactors or transcription factors.

As described earlier in this Commentary, mechanical signalsfrom outside the cell are reflected in alterations in proteinconformations, modifications and expression levels, and these can

broadly affect cell morphology. Taking these changes further, it isof particular interest to understand how external factors drivestem cells to commit to specific lineages, with far-reaching

implications for therapeutics and tissue engineering. Populationsof MSCs can be expanded in culture in an undifferentiated state,but they can differentiate into mesenchymal lineages, includingfat, cartilage, muscle and bone, in a manner that is dependent on

external cues, such as the presence of nutrients, growth factorsand cytokines, cell density, spatial constraints and mechanicalforces (Pittenger et al., 1999). It has been shown that cell shape

influences cell fate by modulating the activity of the smallGTPase RhoA, with round cells being predisposed towardsadipogenesis and well-spread cells more likely to enter the

osteogenic lineage (McBeath et al., 2004). Here, RhoA was foundto drive commitment to a specific lineage in conjunction with itseffector Rho-associated protein kinase (ROCK), through its effecton cytoskeletal tension.

Cell fate can be influenced by the stiffness of the ECM (Engleret al., 2006), and we have recently shown that this effect can bemodulated by the nuclear lamina (Fig. 4A; Swift et al., 2013b).

MSCs cultured on soft hydrogel substrates are biased towardsadipogenesis, but the extent of adipogenesis, as determined bystaining with Oil Red O, is doubled when combined with the

knockdown of A-type lamins. Likewise, a cooperative effect betweenstiff substrate and lamin-A overexpression enhances osteogenesis.Stiff substrate has been found to drive the translocation of the

transcription factors RARG and Yes-associated protein 1 (YAP1) tothe nucleus, thus directly regulating the transcription of LMNA andtriggering a differentiation-inducing signaling cascade (Dupont et al.,2011). Culturing MSCs on stiff substrate also increases the protein

levels of cytoskeletal components, consistent with greater activity ofserum response factor (SRF) (Connelly et al., 2010; Ho et al., 2013),and, in combination with a stiffer nucleus, this further increases

cytoskeletal tension. Translocation of molecular signal carriers is arecurring motif in mechanosensitive pathways that has been shown tooccur during the transfer of ions and changes in osmotic pressure

(Finan et al., 2009; Irianto et al., 2013; Kalinowski et al., 2013), as


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well as during the migration of protein factors. Protein translocationcould be driven by a change in the concentration of binding sites,(e.g. on A-type lamins or emerin; Ho et al., 2013; Swift et al., 2013b)

or, conceivably, by protein modifications (e.g. YAP1 nuclearlocalization can be stimulated by phosphorylation of the protein;Murphy et al., 2014). Additionally, transient breakdown of thenuclear envelope in laminopathic cells, perhaps as a consequence of a

reduced robustness under conditions of mechanical stress, has beenshown to allow the ingress of transcription factors such as RelA (DeVos et al., 2011).

The ability of lamin and its binding partners to tether to DNAhas led to interest in its role in chromatin organization andregulation (Guelen et al., 2008; Kim et al., 2011; Kind et al.,

2013; Lund et al., 2013; Meuleman et al., 2013; Zullo et al.,2012). Lamina-associated domains (LADs) located at the nuclearperiphery are typically associated with low levels of gene

expression, whereas actively transcribed euchromatin is usuallyfound in the nuclear interior. These conserved spatialrelationships within the nucleus give rise to defined‘chromosome territories’ (Cremer and Cremer, 2001; Iyer et al.,

2012) and to transcriptional hotspots within specific locations(Fraser and Bickmore, 2007). Although chromatin and DNA aregenerally considered to make negligible contributions to overall

nuclear mechanics (Guilluy et al., 2014; Pajerowski et al., 2007),particular cases are emerging – for example in ESCs passingthrough a metastable transitional state before differentiation –

where the condensation state of chromatin can becomemechanically significant (Pagliara et al., 2014). It is not yetfully understood which proteins could give rise to mechanically

responsive locally defined structures and organization within thenucleus, nor how a protein as ubiquitously expressed as lamincould play a part in such specificity. Knowledge in this field willcontinue to improve as new experimental methods and models

emerge to allow the study of protein-mediated changes inchromatin organization in response to perturbation of the

system (Shivashankar, 2011; Talwar et al., 2013). However,based on current work, we have hypothesized that the effect oflamin on nuclear mechanics could determine the sensitivity and

timescale of nuclear reorganization in response to stress (Fig. 4B;Swift et al., 2013b).

Cell migration is slowed by the nuclear stiffness needed toprotect chromatinAs the nucleus is generally the largest and stiffest organelle, it canbe a limiting factor in the migration of a cell through the three-

dimensional ECM. This means that the mechanical properties ofthe nucleus can have regulatory roles in certain processes, such asdevelopment, wound healing, hematopoiesis, cancer metastasis

and others (Fig. 5A, left panel). Studies of migration throughnarrow pores that mimic those in tumor tissue, migration throughwhich requires the deformation of the nucleus, demonstrated a

dependence on lamina composition – migration was limited whenlamin-A was overexpressed, but was promoted by a ,50%knockdown of the protein (Harada et al., 2014). However, a moreeffective knockdown to ,10% of normal protein expressionlevels was found to cause apoptosis, underscoring the importanceof lamin in providing physical protection to the nucleus (Fig. 5A,middle panel). Consistent with earlier observations that A-type

lamin and B-type lamin contribute primarily viscous and elasticmechanical properties to nuclei, respectively (Fig. 2), nuclei inwhich high A-type lamin levels dominated the mechanical

characteristics were observed to recover slowly followingdeformation, maintaining an elongated morphology afteremerging from the pores (Fig. 5A, upper-right panel). By

contrast, nuclei with dominant levels of elastic B-type laminsrapidly returned to their more spheroid pre-migratory shapesfollowing deformation (Fig. 5A, lower-right panel).

Cell migration is an important part of the development process,

and it is possible that the elasticity imparted by lamin-B is neededto allow nuclei to recover from the deformation (typically

Cell fate is influenced downstream of lamin-A

LMNA LMNA

A-type lamin level determinesthe rate of deformation when

the nucleus is stressed

New chromatinand lamina contacts

A B

Soft matrix Stiff matrixLow A-type lamin High A-type lamin

Balled-up cells Spread cells, stress fibersCytoplasmic RARG and YAP1 Nucleoplasmic RARG and YAP1

Adipogenesis Osteogenesis

Chromosome territories

Interchromatin contacts

Lamina-chromatin contacts

Tension

Fig. 4. Decisions of cell fate downstream of the regulation of A-type lamin. (A) MSCs cultured on soft and stiff substrates take on different phenotypesand are biased towards alternative cell fates (Engler et al., 2006). On soft substrate, MSCs are rounded and exhibit small nuclear and cellular areas, and thenuclear lamina is thinned (thin red nuclear outline) by a stress-sensitive phosphorylation-feedback mechanism (Fig. 3B, left panel; Swift et al., 2013b). Thetranscription factors RARG and YAP1 (Dupont et al., 2011) remain in the cytoplasm, and adipogenic cell fate is preferred. On stiff substrate, cells spreadextensively, and the nuclei are pinned down by well-developed stress fibers (gray). A-type lamin is less phosphorylated under strain, thus strengthening thelamina (thick red nuclear outline). RARG also translocates to the nucleus, increasing LMNA transcription. Activity of the transcription factor SRF(downstream of A-type lamin) increases the expression of cytoskeletal components (Ho et al., 2013). Under these conditions, YAP1 translocates to the nucleusand cells are more likely to undergo osteogenesis. On both soft and stiff substrates, the effects of ECM elasticity and the levels of lamin cooperate to enhancedifferentiation; knockdown of A-type lamin on soft substrate leads to more adipogenesis, and lamin-A overexpression on stiff substrate leads to moreosteogenesis. (B) Transcriptional activity is believed to be regulated by conserved interchromatin contacts that give rise to the spatial ordering of chromosomes(chromosome territories shown here in different colors, Cremer and Cremer, 2001). A-type lamin can interact with DNA directly (lamina–chromatin contacts)or through protein intermediaries (Simon and Wilson, 2011), but could have additional regulatory roles by mechanically determining the extent and rate that thenucleus deforms under tension, a process that could lead to the formation of altered interchromatin and lamina–chromatin contacts. Arrowheads indicate thedirection of tension.


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elongation) that occurs during migration, perhaps explaining whythe brain fails to develop in lamin-B-knockout mice (Coffinieret al., 2011; Jung et al., 2013; Kim et al., 2011). Neutrophilic cells

also have very low levels of nucleoskeletal proteins to allow theirdeformation as they squeeze into confined spaces (Olins et al.,2009; Rowat et al., 2013), and indeed, the composition of thenuclear lamina is continuously regulated during hematopoiesis

(Fig. 5B; Shin et al., 2013). We hypothesize that bydownregulating components of the lamina, white blood cellscompromise their robustness in favor of mobility, and that this

contributes to the short lifetimes of many of these cells incirculation. Cancer metastasis is an equally complex process thatdepends on factors including the remodeling of the ECM and the

capacity of the nucleus to deform (Harada et al., 2014; Wolfet al., 2013). Other work has shown that the ability of myosin-IIto deform the nucleus can be a decisive factor in limiting glioma

migration into brain tissue (Beadle et al., 2008; Ivkovic et al.,2012), but cancer cells in general show no universal lamina

phenotype (reviewed in Foster et al., 2010). Although low levelsof A-type lamin have been correlated with increased reoccurrenceof colon cancers (Belt et al., 2011), A-type lamin was also found

to be upregulated in certain skin and ovarian cancers (Hudsonet al., 2007; Tilli et al., 2003), and higher expression of theselamin proteins has been associated with better clinical outcomesin breast cancer (Wazir et al., 2013). Our own studies of tumor

expansion in mouse flank have been suggestive of an associationbetween moderately reduced levels of A-type lamin and increasedinvasiveness into the surrounding tissue, but a more complex

relationship between the level of A-type lamin and clinicalprognosis might be explained by the tenuous balance between theeffect of the lamina on nuclear deformability compared with that

on cell survival.

Conclusions and prospectsWe have sought to emphasize the underlying importance ofnuclear mechanics in the context of tissue function, considering

A Nuclear mechanics influence 3D cell migration

Seru

m

ECM

Cell mass

Nuclei

Bottom

Top

10 μμm

10 μμm

Low lamin A:B ratio

High lamin A:B ratio

Hematopoieticstem cellprogenitor

Whiteblood cell

Redblood cell Platelets

Enucleation

MegakaryocyteErythroidprogenitor

Granulocyte,monocyte and

lymphocye

Lamin-A expression

Knockdown Overexpression

Mic

ropo

re m

igra

tion

Very low lamin-A:apoptosis

Lamin-A KD:increased migration

Lamin-A OE:impeded migration

WT

Bone marrow:higher lamins

Peripheral blood:low lamins

Shear

B Lamina composition regulates hematopoiesis

Fig. 5. The influence of the mechanical properties of the nucleus on cell migration. (A) Left: as the largest and stiffest organelle in the cell, the nucleus canact as an ‘anchor’, preventing cell movement through the ECM or into the surrounding vasculature. Middle: to model migration through the ECM, cells areinduced to pass through 3-mm pores, a diameter sufficiently small to require deformation of the nucleus (inset). Lamin-A overexpression (OE) inhibits migration,whereas knockdown (KD) increases migration to five times that of wild-type (WT) cells; however, highly effective knockdown leads to substantial apoptosis.Thus, extremely low or high levels of A-type lamin are unfavorable for cell migration, an observation that potentially impacts upon the understanding of processessuch as cell migration during development and cancer metastasis. Right: lamin-A-rich nuclei (upper panel) show a persistently elongated morphology uponemerging from the pores (yellow arrowheads), whereas lamin-B-rich nuclei (lower panel) rapidly recover their shape (Fig. 5A adapted from Harada et al., 2014.Originally published in The Journal of Cell Biology, doi: 10.1083/jcb.201308029). (B) The effect of lamina composition on nuclear deformability duringhematopoiesis. Stem cells that are retained in the marrow niche have higher lamin levels than differentiated blood lineages (Shin et al., 2013). A downregulationof nuclear cytoskeletal components in granulocytes, for example, ostensibly makes the cells better suited for passage through narrow blood vessels, but the lackof nuclear stability might contribute to their relatively short circulation times (Olins et al., 2009).


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how they determine the protective properties of the lamina,influence cell fate and also regulate cell migration. In

understanding that one of the key functions of lamins is toensure that the mechanical properties of the cell meet thedemands of a tissue – either directly or indirectly, by drivingbroader changes with regard to cell fate – we are essentially

allocating lamin a role in stress response (Zuela et al., 2012). Theresponse to cellular stress is classically thought of in terms of howcells mitigate heat shock, which can otherwise result in high

levels of unfolded proteins (Hartl et al., 2011), but mechanicalstress can also cause protein unfolding with associated loss offunction (Swift et al., 2013b). Another recent review highlighted

the similarities between cellular responses that involve theexpression of heat-shock proteins and those that drive structuralintermediate filament proteins (Toivola et al., 2010). Just as the

lamina responds to mechanical inputs from the ECM, mechanicalstretching is sufficient to induce the expression of the molecularchaperone heat-shock protein HSP70 (Silver and Noble, 2012).However, we are still a long way from fully understanding

cellular protection mechanisms and the way in which stressresponse pathways affect the regulation of structural featureswithin the cell. Nonetheless, it is apparent that nuclear biophysics

has an important role to play.

AcknowledgementsWe thank our colleagues P. C. Dave P. Dingal, Irena L. Ivanovska and StephanieMajkut at the University of Pennsylvania for helpful comments.

Competing interestsThe authors declare no competing interests.

FundingWe appreciate support from the U.S. National Institutes of Health, the U.S.National Science Foundation and the University of Pennsylvania’s researchcenters (Materials Research Science and Engineering; Nano Science andEngineering; Nano/Bio Interface). Deposited in PMC for release after 12 months.

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