Mechanosensitive mechanisms in transcriptional regulation

The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters

Citation Mammoto, Akiko, Tadanori Mammoto, and Donald E. Ingber. 2012. “Mechanosensitive Mechanisms in Transcriptional Regulation.” Journal of Cell Science 125 (13): 3061–73. https://doi.org/10.1242/ jcs.093005.

Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41461229

Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Journal of Cell Science o:10.1242/jcs.093005 doi: 3061–3073 125, Science Cell of Journal 1 Mammoto Akiko regulation transcriptional in mechanisms Mechanosensitive Commentary ehntasuto,addsushwmcaia cues life. organogenesis adult cellular mechanical throughout govern maintenance into tissue to how ensure insights to regulation and discuss new transcriptional this these influence In and tissues. review adult mechanotransduction, of and we regulators embryonic important Commentary, equally in on that are control suggests 2) studies transcriptional work (Box chemical most recent forces or transcription, mechanical factors Whereas genetic of highly on mechanisms 1). transcription focused control a is have (Box various regulation in co-regulators process transcriptional II, off their interplay polymerase the this and through and transcription RNA and on of between level manner, the at mediated turning controlled behaviors These by life. spatiotemporally adult regulated throughout switching for are as fate well as cell embryonic organs, or stem of tissues maturation differentiated embryogenesis. the terminally identity for into during cells necessary cellular are maintain times that functions and precise and confer at programs locations Transcriptional apoptosis) specific and specific the migration exhibit in of differentiation, that growth, result types (e.g. a cell behaviors as various constructed of orchestration are complex architecture organ and Tissue Introduction words: Key ( Gardel – L. dimension Margaret and third Schwarz the S. ‘Deconstructing Ulrich articles: ( by ( related al. mechanotransduction’ Labouesse see et ( Michel please Roca-Cusachs Chen and reading, S. Pere Zhang Christopher further by and For pathways’ Baker Mechanotransduction. M. molecular Brendon on mechanical by Minifocus medicine. cues’ tissue a cellular regenerative and alter of and cell mechanisms microenvironments part engineering control of is transcriptional control tissue of article mechanosensitive the maintenance to these This in approaches the involved of new understanding to is to deeper it contributes how transcription A lead as life. should gene well adult of as embryogenesis and organogenesis, control for embryogenesis and crucial mechanical throughout formation are function the pattern that fate, how activities cell transcriptional review during orchestrate of we determination to changes pluripotency, Commentary, co-regulators indirectly cues, and or this mechanical mechanics directly their (ECM) In nucleus that matrix organogenesis. the extracellular indicates and and to in evidence transmitted alterations factors stress), are Accumulated shear shape, activities. transcription or cell compression transcriptional in tension, signals, (e.g. of constructed forces are control adhesion physical regulation organs include transcriptional spatiotemporal and which cues, tissues how the (3D) three-dimensional on through chemical how focused explain maintained has to between sufficient and work not most interplay is alone past, organogenesis, signaling complex for chemical the However, as In development. well the organs. as development, and embryonic from tissues for stem adult crucial results in is in transcription and regeneration of cells and level embryonic adaptation, the in at functional differentiation expression and gene self-renewal of pluripotency, control Therefore, of cells. maintenance the to contributes regulation Transcriptional Summary work this to equally ` contributed authors *These 3 2 rnils ySre uhrvadFeeikScs( Sachs Frederick and Sukharev Sergei by principles’ uhrfrcrepnec ( correspondence for Author avr colo niern n ple cecs abig,M 23,USA 02139, USA MA 02115, Cambridge, MA Sciences, Boston, USA Applied University, 02115, and Harvard MA Engineering at Boston, of Engineering School, School Inspired Medical Harvard Biologically Harvard for and Institute Hospital Wyss Children’s Program, Biology Vascular 02 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2012. ehnclfre rncito,Se el,Ebys atr omto,Got,Ctseeo,Nces rsrs,Cl shape Cell Prestress, Nucleus, , Growth, formation, Pattern Embryos, cells, Stem Transcription, force, Mechanical 1, ,Tdnr Mammoto Tadanori *, [email protected] .Cl Sci. Cell J. 125 0934) Uie esad–itgaigteatnctseeo n elmti dein ncellular in adhesions cell–matrix and cytoskeleton the integrating – stand we ‘United 3039-3049). , .Cl Sci. Cell J. ) 1, n oadE Ingber E. Donald and * .Cl Sci. Cell J. 125 3075-3083). , .Cl Sci. Cell J. 125 0533) Sgaln hog ehnclipt oriae rcs’b Huimin by process’ coordinated a – inputs mechanical through ‘Signalling 3025-3038). , 125 0136) Mlclrfretasuto yincanl iest n unifying and diversity – channels ion by transduction force ‘Molecular 3051-3060). , .Cl Sci. Cell J. tecigidcdb ylcmcaia tanlasto leads and strain ESCs, cell mouse mechanical Moreover, in expression 2007). cyclic gene al., OCT4 by et of downregulation Peerani pluripotent induced 2011; these stretching al., 1). of vitro et in and (Fig. cultured expression ESCs (Hemsley mouse (sparse) 2009) flattened higher rounded than factors exhibit transcription compact, Tam, ESCs of and human cultures dense (Rossant NANOG, Importantly, and The pluripotency SOX2 POU5F1), cavity. as factors, promote known transcription (also transcriptional of the OCT4 stable sets including a specific into whereby establishes surrounding circuit, ICM the regulatory the liquid against and ICM pellucida, the of the zona pushes of liquid expansion secretion to of the rise the of accumulation and result gives embryogenesis, a blastocyst as the blastocoel mammalian (ESCs) of cells (ICM) in stem mass embryonic Early cell development inner 2009). organ totipotent Wozniak 2010; and Chen, Ingber, and tissue in and Mammoto 2011; for Farge, required in changes (reviewed are and that migration sense signals differentiation, intracellular growth, apoptosis cell into in cells alterations them drive transduce that individual and forces mechanical development, During embryogenesis early during control transcriptional of determinants Mechanical 125 1,2,3, 0532) Fnigtewaetln xlrn integrin-mediated exploring – link weakest the ‘Finding 3015-3024). , ` o Dculture 3D how 3061 Journal of Cell Science rdet sarsl,temdlpeit httetsu ilgrow 2005). will Shraiman, tissue 2007; the morphogen al., that the et predicts of (Hufnagel model edges uniformly the will the result, wing a beyond As the extend gradient. of cells periphery the al., the et when growing (Chen at slow area growth the central cell the Meanwhile, in of growth 1997). cell parenchyma suppress to central back studies feeds the modeling in Drosophila cells computational during that instance, size suggest organ orchestrate For and development. to growth tissue cues proliferation, the chemical for embryogenesis. early crucial with during are patterns spatiotemporal that of concert formation controls biochemical in and transcriptional act mechanical that forces suggest observations These 2009). al., et Gonzalez encoding gene the Twist-dependent of through transcription Snail factor transcription zinc-finger (Desprat the differentiation midgut 2A). (Fig. subsequent 2008) for al., et crucial is helix-loop-helix and basic the of factor stomodeal transcription transcription of the pole activates anterior of and the cells, in translocation in junctions cell–cell nuclear from deformations Src42A-dependent physiological triggers (GBE) instance, For during embryonic 2003). patterning thereby (Farge, and tissue expression, gene cells of individual govern to patterns to back control feed sufficient mechanically can embryo be to in the changes to of Importantly, shape appear physical form. genetic the tissues not complex internal do these how However, transcriptional cues explain the 2010). chemical at and Basler, mediated programs and is (Schwank process this level that and size the and tissue determine in pattern, gradients morphogen stages that developmental revealed have later of Studies embryo the and in pattern micromechanical size tissue determine local cues Mechanical the by embryo. modified the can in the and pluripotency environment that for maintained suggest necessary findings the be is inside These that tension 2010). regulation cytoskeletal al., transcriptional of et level (Chowdhury the cell on dependent is this 3062 srlee uigai lnainin elongation mechanical axis to during response relieved in is tension locally mechanical when membrane Importantly, recruited the from disappears 2007). distortion, is al., which et Myo-II, (Kolsch invagination constriction subsequent apical molecule, reinforces is and signaling which downstream Twist T48, another drives 2005). activate transmembrane subsequently al., also which to et known membrane, (Dawes-Hoang apical invagination mesoderm the II at and pathway (Myo-II) (Rho–ROCK) coiled-coil Rho-associated, 1 and kinase Rho protein signals the containing These of activation 2009). local al., to et lead (Pouille Fog of signaling downstream activating pathways thereby by and concentration cells endocytosis, extracellular mesodermal the Fog enhancing the of inhibits membrane constrictions apical Snail-dependent the that in tension Mechanical generated 2009). is al., et (Martin the protein by Fog stabilized secreted subsequently are and pulsed, apical stochastic are induces that Snail constrictions First, 2B). (Fig. 2009) al., 2007) et al., (Pouille et (Seher invagination mesoderm with begins process this ehnclce locnrbt otecnrlo cell of control the to contribute also cues Mechanical in Gastrulation ora fCl cec 2 (13) 125 Science Cell of Journal Drosophila igbcm opesd u htmechanically that cue a compressed, become wing Drosophila Twist ise asdb emadextension germband by caused tissues hc sivle nptenformation pattern in involved is which , scnrle yTiti ocr with concert in Twist by controlled is oddgastrulation Folded Drosophila Drosophila Drosophila morphogenesis (Fernandez- Drosophila ( Fog ,and ), wing b - eursa natatnctseeo AsinadKen 2008; the it in Klein, changes observation, and this and with Consistent contacts, (Assoian 2007). cytoskeleton al., cell–cell et actin Klein and intact an (ECM) from requires inputs matrix mechanical to extracellular response to in sensitive the and rate is proliferative Oh cues, their mechanical 2007; alter external pathway, al., to This 2010). cells et al., enables et (Dong Ren which 2009; cell 2C) Irvine, and (Fig. to the Oh 2008; Yap1, E as Irvine, leads cyclin such (and which regulator genes, cytoplasm, cycle target Yki the of phosphorylated downregulation in transcriptional retained in being both results respectively) In Mymryk, signaling 2010). and al., (Dick Hippo mammals) et co- in Zhao transcriptional Yap1 2011; the (Yki; and Yorkie (Mats), activator and 1 (Sav) activator-like salvador kinase protein MOB scaffold co-factors kinases, (Wts) their Warts with and The (Hpo) together loop. Hippo feedback the this of composed in in is involved growth pathway be organ to of appears vertebrates, regulation and correct the for crucial opeetr N euneb N oyeaeI htbinds that II polymerase RNA by sequence DNA complementary Transcription: transcription of Regulation 1. Box n euae elfate. compression cell resist regulates transduction cells) and that signal neighboring controls structures Prestress or filipodia). ECM load-bearing , (e.g. the internal to (e.g. by cell and by the resisted of Pulling are tethers balance mechanism. external contractile tensegrity force within a mechanical generated through forces a cytoskeleton of the establishment within the contractile integrins, by the (e.g. generated tensional of receptors prestress: adhesion Cell shortening transmit surface the which cell cadherins). of across filaments, result forces actomyosin a as cytoskeletal cells other force: traction force. Cell applied the of direction force: force. applied Tensional the of direction the hematopoietic force: and Compressive cells the of endothelial determination cardiomyocytes, the cells. in of through role blood fate key pumping a cell heart has circulation the systemic by the generated stress shear (e.g. The organs living stress: infuse Shear or lung). perfuse or that vessels air) blood or blood (e.g. gases pressure: Hydrostatic regulation in transcription involved of forces Mechanical 2. Box transcription. of rate the downregulate strand. or DNA up- respectively, the to, to RNA II co-repressor: polymerase or RNA Co-activator of of binding recruitment the regulating gene. block , a regulation: of associated regions Transcriptional or promoter other the to promote with II polymerase combination factors the in on sequence transcription or promoter target Alone its to DNA. affinity high with binding by gene. a factor: of Transcription region promoter the to h ip aha,acnevdsgaln aha htis that pathway signalling conserved a pathway, Hippo The rcinlfreo li lwo h ufc fcells. of surface the on flow fluid of force frictional h ytei fa N oeuefo a from molecule RNA an of synthesis the tblzn smti eso ntecl htis that cell the in tension isometric stabilizing uln oc htlntesmtrasi the in materials lengthens that force pulling seetdo h deint h C and ECM the to adhesion the on exerted is euaoypoenta euae transcription regulates that protein regulatory uhn oc htsotn h aeilin material the shortens that force pushing ehnclfreapidb lisor fluids by applied force mechanical otostert ftasrpinby transcription of rate the controls soit ihtasrpinfactors transcription with associate Drosophila n ie active mice, and Drosophila Journal of Cell Science h rncito atrSA5 ciae h eetr n ed to leads and receptors the activates STAT5, factor transcription of local translocation the nuclear the the following to and receptors This, prolactin hormone. three-prolactin exposes laminin, into protein ECM by physical cells induced the are development: epithelial which structures, acinar gland mammary polarized the (3D) dimensional mammary mouse mouse of in reorganization during complex changes observations which supported a – is by theory signals This through through chemical control. transcriptional into alter governed subsequently back largely feed be that manifest microenvironment to actions cues chemical seem which their fate in mechanism 2D). cell subsequent mechanochemical (Fig. the 2011) and al., determination distortion of organ-specific organ-specific et and cell patterning (Mammoto orchestrate developmental signaling of Thus, Rho that result of of a inhibition factors expression as transcription protein morphogenesis the of triggers turn, sets condensed in the cell of This, ‘formation and of the mesenchyme’. as areas (FGF8 known process defined a factors generate in compaction that motility respectively) of repulsive 3F, gradients semaphorin and morphogen attractive produces epithelium opposing al., dental in et formation the tooth during (Landsberg mouse, Furthermore, 2010). boundaries al., and et compartmental Monier Myo-II, 2009; discrete and formation these ROCK the to Rho, contributes of – by adhesions cell–cell controlled on tension is exerts which – tension tbetsu tutrsdrn mroeei Dhane al., et in into (Dahmann patterns Studies embryogenesis early during these 2011). structures of maturation expression tissue the these stable for by crucial defined is are tissue patterns that of boundaries because determination the important is maintaining the This fates. to cell organ-specific and contribute boundaries of also external that boundaries cues suggests the evidence physical mechanical Recent 1992). limit precise al., distinct et within (Small produce spatially tissues fates and gradients cell genes organ-specific target-differentiation These target of of 1969). expression responses (Wolpert, concentration-specific genes by of patterns expression into converted are gene embryo the in gradients Morphogen during fate development cell the of determination organ-specific of control stimuli Mechanical environmental to response 2011). in al., et the growth mechanical (Sansores-Garcia to cell cytoskeleton-dependent leads of which this regulation, inhibition transcription for in pathway role signaling a further This cell Yap1. highlights alter through signaling also Hippo can modulating cytoskeleton by growth actin the of organization pluripotency. physical for crucial are that (TFs) factors transcription specific pluripotency. induces and which control transcriptional Mechanical 1. Fig. ((no non-compacted Drosophila BlastomereBla n-c sto omp mer act e ed) aervae htcytoskeletal that revealed have ) ((co compacted MorulaMo mpa h xadn lsoolpse h ne elms IM gis h ue oapluia(ZP), pellucida zona outer the against (ICM) mass cell inner the pushes blastocoel expanding The r ula cte d) ) Trophoectoderm dl rasadognsses nldn er Gonnike al., developmental et most (Groenendijk during of heart including function role systems, the organ maintaining a and for organs crucial have adult also are only but not processes, forces Mechanical homeostasis and development organ during control transcriptional Mechanosensitive 2009). al., et (Xu lineage cell mammary-specific b xmlso hsfr fmcaoeuaini eeatorgan relevant in mechanoregulation of form systems. this provide we of Below, 2005). examples Tidball, 2010; musculoskeletal Ogawa, and and and Wallace, 2009) (Huang system Basson, (Culver and 2009), and (Hooper al., (Gayer et vessels tract North lungs 2009; gastrointestinal al., 2005), blood et (Adamo al., system 2011), hematopoietic et 2006), Shiu Parker, 2010; and Dickinson, McCain 2007; nohla el Lee l,20)–hsbe hw ohave to shown 2009). been al., et has (Vermot in – morphogenesis 2006) valve genes in al., roles atheroprotective et crucial (Lee and cells antithrombotic endothelial angiogenic, expression the of orchestrates (Moskowitz that factor transcription development Kru flow-sensitive zebrafish, formation In cushion 2011). valve al., endocardial et co-regulate they controlling mouse, by In cascade. signaling lo el,atvtn eaooei tmclsi the in cells of stem formation heart the hematopoietic of on activating switches initiation also the cells, flow embryo, blood blood mouse and the pumping in Interestingly, system Hematopoietic factor growth transforming this protein morphogenetic mediate and bone the partly of another (BMP) part to SMAD4, is with that appears factor interacts 2010), transcription and GATA4 in al., example, 2011) flow blood For Yutzey, et in response. and (Huang changes the Wirrig heart by 2003; activated the al., also B-type is et which Hove GATA4, as 2004; al., cardiac such et 2001). to al., hypertrophy, et contribute (Marttila that (BNP) that ventricular peptide genes transcription natriuretic and of of expression remodeling the mediator a al., as regulates implicated et load-responsive been (Hautala also 3) has GATA4 (Fig. mechanical 2002). rats al., in et through Hautala ventricles 2001; and the of afterload stretching cardiac direct by in activated that is increases and factor vasopressin-induced 2002), transcription (Bruneau, a development heart is regulates (GATA4) 4 protein GATA-binding Heart BlastocoelBla csi xrsin hc nue ifrnito fclsit the into cells of differentiation induces which expression, -casein omto ftehatvlei lofo-eedn (Bartman flow-dependent also is valve heart the of Formation BlastocystBBlaBlasto ehnsniietasrpin3063 transcription Mechanosensitive sto ZP cys y t pe-iefco KF)–another – (KLF2) 2 factor ¨ppel-like ( (OCT4, SOX2,NANOG O I ICM TFs forpluripotencyT CMC CTC FsF M T s 4 fof ,

b (TGF- ) b TGF- ) b Journal of Cell Science ihl uigmsnhmlcnesto ntohdvlpet h eutn ehnclcmato-nue hne ncl hp nuest ftr of sets induce shape ce cell mesenchymal in emp causes morphogenesis. changes By This organ-specific compaction-induced gradient. respectively. for mechanical morphogen cells, resultant crucial the mesenchymal The are ce of repulse development. that and edges and tooth attract the factors decreased in that beyond is f condensation (red) grown E, transcription mesenchymal 3f have during cyclin the semaphorin they tightly of as and because phosphorylation such (green) proliferation ( FGF8 to genes, their uniformly. morphogens leads target grows slow antagonistic tissue and periphery Yki whole the pathway of the at Hippo mechanisms, activity two cells the transcriptional these time, activates Consequently, same which nucleus. the cells, the At ac these into inhibited. This in translocation Mod tension. actin its Twist. membrane of of prevents in control remodeling which ( the increase in 2010). under an Ingber, expressed results through and is This (Mammoto endocytosis Fog compressed. invagination. 2010 Fog and Ingber, of cruc constriction and apical inhibition Mammoto is stable induced from which to permission mechanically leads Twist, which a ( factor pathway, to transcription 2010). signaling lead II of the Ingber, Fog–Rho–ROCK–Myo constriction translocation encoding and apical the gene (Mammoto of to the 2010 pulses leads of Ingber, unstable expression that and induces process Mammoto (GBE) mechanotransduction from extension Src42A-dependent permission band a germ through formation. of differentiation pattern result midgut embryonic a during as transcription compression of mechanical control Mechanical 2. Fig. 3064 compression GBE, A C ora fCl cec 2 (13) 125 Science Cell of Journal Midgutdifferentiation Tissue growth

Active Hippopathway Morphogen gradient P Periphery Center Yki Src42A inhibition β Growth -catenin differentiation (e.g. cyclinE) Yki target Twist Midgut genes

Tissue growth D elcmato.Drn et eeomn nmue h al etleihlu D)poue the produces (DE) epithelium dental early the mouse, in development teeth During compaction. Cell ) Repulsion B D Snail-dependent Mesoderminvagination Cellcompaction membrane tension membrane Basement Upregulation oforgan-specific C Snail DE isegot.Drn iggot in growth wing During growth. Tissue ) B Remodeling Apical constriction eoemivgnto.I the In invagination. Mesoderm ) transcription factors of actin (e.g. Pax9,Msx1) Invagination compaction Mechanical Tension Rho/ROCK ( A igtdfeetain In differentiation. Midgut ) Twist Mesenchymal cells Downregulation Fog of RhoA Attraction Drosophila b ctnnit h ulu.Mdfe with Modified nucleus. the into -catenin Drosophila Drosophila Key eoem h Snail-dependent the mesoderm, EDental epithelium DE el ntecnrlrgosare regions central the in cells , neirsooelcells, stomodeal anterior Myosin II Cadherin Repulsive morphogen Fog Fog receptor Mechanical tension Attractive morphogen Actin lgot is growth ll anscription l opack to lls iae the tivates co Yki, actor fe with ified loying a for ial Journal of Cell Science lwaecnrlt h oto ftasrpinlatvte that activities transcriptional of control blood the 2010; by and to al., generated central forces et mice mechanical Lichtinger are Thus, in 2009; flow 2009). al., (NO) al., et et oxide North (Adamo by is 3) nitric induced (Fig. effect is of zebrafish that This RUNX1 production the 1996). factor flow-sensitive transcription of Dzierzak, the and origin by mediated (Medvinsky the aorta region, dorsal (AGM) aorta–gonad–mesenephron us(ot ta. 01 edlo,20;Mno 00.Before 2000). Minoo, 2000; mechanical Mendelson, to 2001; sensitive al., et highly (Costa is cues development lung Embryonic Lung Mechanical ( inducer angiogenic 61 1999). cysteine-rich the al., of transcription mechanosensitive et induces strain the (Morawietz by EGR1 in level factor transcriptional arteries transcription at – pressure the regulated blood also in of changes is as remodeling such – cells, loads mechanical muscle to response smooth TFII-I 2009). vascular al., et and (Mammoto In cells endothelial GATA2 in GTF2I) factors as known transcription (also two of between ECM balance the activities in alter changes which compliance), by or stiffness regulated (e.g. mechanics are microvessels new of formation 2003). al., et survival (Urbich cell endothelial and for promoter, crucial VEGFR2 its is regulation encoding to transcriptional this SP1 gene factor transcription the the of of binding maintainingthrough transcription for shear the fluid activates addition, crucial In stress 1998). are al., al., that et et (Ahmad homeostasis molecules Martin vascular Ozawa 2000; adhesion 2004; al., al., and et (Allport et 1997) cytokines Davis several 2009; 2004), al., al., et et (Balligand eNOS Activated as 2005). such al., et Tzima 2005; NF- flow- al., et (Orr (VEGFR2); cascade activates signaling 2 cells endothelial factor the NF- of growth distortion mechanical endothelial mediated vascular adhesion cell–cell and mechanosensory (VE)-cadherin endothelial a vascular PECAM-1, containing through complex also stress cells shear Endothelial 2000). sense al., blood maintain et they (Gimbrone homeostasis where cells, vessel endothelial (NF- in SSREs to B (EGR1), kappa factor nuclear as such factors, transcription stress mechanosensitive of shear binding shear-stress-responsive Fluid regulates regions. by promoter their regulated within (SSREs) are elements 1996), al., al., et et (PECAM1) (Almendro 1 (Davis molecule NOS3) adhesion cell as endothelial platelet known and also 2004) 1993), (eNos, al., 3 synthase et oxide (Resnick as nitric (PDGFB) such homeostasis, B that vascular factor genes for growth mechanical of platelet-derived crucial transcription are cyclic the that on proteins and shear encode fluid pressures of effects to pulsatile The exposed strain. stresses, constantly are shear vessels fluid blood within cells Endothelial vessels Blood system. circulatory the of development govern CB)floigsiuaino h OKadtep38MAPK 2001). the al., by and et (Cattaruzza mediated ROCK 3) the (Fig. is pathways of protein CCAAT/enhancer-binding stimulation this following and (CEBP) level (AP1) 1 transcriptional protein B the activator arterial endothelin blood-pressure-dependent At of in expression involved remodeling. has protein is cells the which muscle increase receptor, smooth In to aortic shown 2006). rat Goppelt-Struebe, been of stretching and cyclic (Chaqour addition, cells muscle smooth uigagoeei,VGR rti ytei n the and synthesis protein VEGFR2 angiogenesis, During k k CYR61 peuae h xrsino ee htecd proteins encode that genes of expression the upregulates B MAPK14) as known (also MAPK integrin–p38 the through B ,acuilgn o aclrdvlpetadrpi in repair and development vascular for gene crucial a ), k )aderygot epne1 response growth early and B) htapa oifunefrainadmtrto falveolar of maturation changes and physical humans formation dynamic influence undergoes in breathing to also to appear lung age transition the that the gestational birth, mature During at more in 1987). for air a al., and example, et expected alveoli larger (Wigglesworth for of of than 2000). number seen, formation al., increased architecture the (as an et in with lung results Yang lungs atresia) fetal 2008; laryngeal (SRF) the al., is congenital factor of et process response serum (Badri This Overdistention the muscle, factor development. of smooth activation bronchial transcription airway the for in by crucial mediated myogenesis stretching mice drives is Mechanical also 2005). in which al., lung et morphogenesis the Moore of 2002; cytoskeletal branching al., in et lung (isometric (Moore changes prestress affects Rho-dependent tensile (Muraoka of contractility by branching level generated lung the Similarly, of tension) 2000). morphogenesis al., during et al., role et a (Londhe NF- has lung, NF- mouse chicken in In activates embryogenesis lung 2008). of cells during maturation cells enhances epithelial which epithelial 1982). 1996), lung Liggins, Hooper, and and of (Harding Vilos 1986; of stretching al., properties et recoil Physical (Harding elastic fluid tissues the of lung and the secretion epithelium by pulmonary generated the by are pressures intraluminal birth, itnigclsi a htmmc nlto n elto of deflation al., 2005; et and Wang mechanically 1999; inflation al., by 2006). et mimics al., (Gutierrez modulated that respiration during is way alveolus cells, et the a alveolar in II cells have Nelson or distending into studies cells I vitro lung type 2005; embryonic in either rat example, of al., differentiation For that 1987). demonstrated al., et et Wigglesworth (Inanlou structures nt htaecntnl eoee nrsos ocagsin changes intracellular to of target response molecular in Ca a of remodeled Calcineurin, load. production constantly sarcomere mechanical the are contractile to into that leads assembly units their genes and of proteins sets myofibril specific of Ziros expression 2007; alkaline al., and et (Kanno osteopontin 2008). rodents al., sialoprotein, and et of humans bone in expression collagen, phosphatase osteocalcin, I controls transcription including type the subsequently genes, activates phosphorylates differentiation which osteoblasts osteoblast-specific For and RUNX2, to factors. of factor binds transcription deformation which specific mediated MAPK, are mechanical of effects 2006; activation these al., example, of et the Many Robling the 1985). 2009; through 1994; al., Lanyon, within al., et and et (Kahn Rubin muscle Raab-Cullen rats or 1992; and and humans Lanyon, gravity cartilage in by system ligaments, musculoskeletal bones, generated of tendons, formation loading, the joints, stimulates Mechanical similarly movement, pressure 2002). the physical to through al., (IL6) cells 6 et these interleukin AP1 of of factor synthesis NF- Exposure the transcription 2001). modulates also al., the through transcription et cells of gene (Hirokawa epithelial activation instance, gastrointestinal stimulates rat gut MAPK-mediated in For the proliferation exhibit in and to regulation. shown pressure been mechanical transcriptional have organs other mechanosensitive many within systems Tissues musculoskeletal and gastrointestinal The yct nacrfco MF)admoei differentiation myogenic and (MEF2) 2 factor enhancer myocyte iial,drn ifrnito fseea uce the muscle, skeletal of differentiation during Similarly, 2+ k cloui inln ciae h rncito factors transcription the activates signaling –calmodulin aha,wihi rca o u oesai (Kishikawa homeostasis gut for crucial is which pathway, B ehnsniietasrpin3065 transcription Mechanosensitive k ciiyi h eecyealso mesenchyme the in activity B k B Journal of Cell Science i.3. Fig. 3066 matrix Nuclear actin Nuclear e etpg o legend. for page next See C B A ora fCl cec 2 (13) 125 Science Cell of Journal NF- ERK p38MAPK SRF Elasticity (mechanicalstrain)

Shear stress κ B JNK AP1

Rho-GDP

RhoGDI GEFs

GAPs Rho-GTP RUNX1 PAX9

Rho-GDP NO RhoGDI

GEFs GATA2 TFII-I RUNX2

GAPs Compression Rho-GTP MKL2 STAT5 VEGFR2 EGR1 MAPK NF- MKL1 ROCK κ B MEF2 GATA2 MYOD1 SP1 SMAD4 p38MAPK PECAM CYR61 AP1 GATA4 CREB KLF2 PI3K Nuclear pore PKC EGR1 Mechanosensitive Phospholipase ion channel Key

ECM Tension Kinases factors Transcription Integrin αβ Myosin II Cadherin Paxillin Zyxin Actin FAK Nesprin Journal of Cell Science oe atlg n ot.Prso hsfgr eemdfe ihpermission with modified were figure as this such of forces, Parts compressive tooth. bear and normally crucial cartilage are that bone, that tissues MYOD1) of and homeostasis MEF2 activities for RUNX2, transcriptional PAX9, cytoskeletal various example and modulate for MAPK) can (involving and changes GAPs these and Again, GEFs tension. molecules their signaling the GTPases, biochemical across Rho intracellular transmitted of (e.g. are activities alter that also movements can physical ECM or ( gravity prestress. by signaling cytoskeletal generated biochemical and in p38MAPK) changes NO, downstream (e.g. through NF- modulated KLF2, are Various GATA4, SP1) PECAM. RUNX1, these or (e.g. sense VEGFR2 activities cells as transcriptional the such stress, mechanosensors shear fluid through apical forces influence to exposed can are nesprin, cells, as ( endothelial such directly. nucleus, more the activity to transcription molecules cytoskeleton and are the filaments and connect cytoskeletal receptors along that adhesion nucleus the surface to EGR1). on directly and exerted transmitted CREB are CYR61, that SMAD4, forces MKL2, Physical MKL1, STAT5, SRF, AP1, rmMmooadIge,21 MmooadIge,2010). Ingber, and (Mammoto 2010 Ingber, and Mammoto from edt h ciaino rncito atr eg AA,TI-,NF- TFII-I, GATA2, (e.g. factors signals transcription mechanochemical of these activation of the All to acid. lead arachidonic and lipids inositol oto fmoei n sebatcdfeetaini mouse in 2002). al., differentiation et (Rauch osteoblastic cells transcriptional and stem the mesenchymal myogenic in role of crucial al., a Mechanosensitivecontrol et has 2004). also (Friday al., BMP2 et mice of Parsons endocytosis in 2003; al., myogenin et of Friday 2000; expression the inducing by myogenesis mechanical-load-induced mediate which (MYOD1), 1 K,rsetvl,truhscn esnessc sitaellrCa intracellular as such messengers and second PI3K through activate respectively, which modulates PKC, phospholipases, also and integrins channels activating on ion GTPase exerted mechanosensitive and tension GTPases (GEFs) Mechanical small factors (GAPs). Rho exchange proteins and nucleotide JNK), paxillin) guanine and zyxin, its ERKs FAK, and MAPK14, (e.g. PKC, proteins (e.g. adhesion kinases focal as pathways such signaling proteins intracellular involving alter cadherins forces. and external receptors integrin to through cells of response the ( modulates governs hence, internal equilibrium and by mechanical mechanics and This cell cells 2006). neighboring integrin (Ingber, to by structures adhering against cytoskeletal cadherin worked of ECM, are interactions the that by to cytoskeleton generated adhering the are within latter myosin The inside and generated forces. actin is mechanical a tension by isometric which cells of in the state mechanism or tensegrity prestress a tensional compression. through stabilizing and stabilized stress are shear tissues fluid and in strain, control mechanical transcriptional to and response pathways Mechanotransduction 3. Fig. process a in instance, For tissues. diseased repair sometimes ventilator- can and 2003) 2007). al., Wang, et and (Ning 2005; (Kumar injury al., asthma lung et induced 2005), Ray 2004; al., al., et et metalloproteinases. Yang (Agarwal inflammatory arthritis matrix to as lead and such can diseases, responses NOS2) these of as activation Continued known also (iNOS, interleukin-1 as factor necrosis the such tumor (IL1B), increases proteins, forces pro-inflammatory mechanical of normal excessive expression to tissues of of example, exposure muscle for smooth deregulation hypertrophy of a rodents, cardiac activation transcriptional that in In exaggerated results through 1). loading (Table note hemodynamic changes excessive to pathological lead can to control important transcriptional of mechanisms mechanosensitive is It development disease control and transcriptional mechanosensitive of Deregulation A atn(CA)(akadOes 99 hoe l,20) The 2007). al., et Zhao 1999; Owens, and (Mack (ACTA2) -actin hnclsadtsuseprec ehnclsri,fre transmitted forces strain, mechanical experience tissues and cells When ) ttesm ie utie plcto fmcaia force mechanical of application sustained time, same the At a B TF) nuil xd synthase oxide inducible (TNFA), hnahrn el,sc as such cells, adherent When ) C opesv forces Compressive ) k ,ER and EGR1 B, Cells 2+ k B, , b a rdc hs rncitoa leain aeol oeto come only for have cytoskeleton alterations crucial recently. contractile light transcriptional the these are within produce generated at can that or applied surface forces the cell genes mechanical the contrast, which transcription By of through of maintenance. mechanisms varied tissue expression activity and control the the developmental regulate and can factors that demonstrate forces clearly above mechanical described examples multiple The control transcriptional and Mechanotransduction transcriptional the about mechanoresponses. known these is mediate little that (Foker processes However, the atresia 1997). esophageal (Park with al., of rats infants lengthening et human in and in stretching regeneration length esophagus induces the intestinal stretching constant of and in 2004) Similarly, increase al., an et skeletal 2002). to of leads al., treatment intestines 1989b; the et Ilizarov, 1989a; for (Ilizarov, Aarnes humans osteogenesis and dogs enhance bones in deformities on to traction used gradual osteogenesis, is distraction as to referred rshsht (Ins trisphosphate ehnclfre a le rncito yactivating by transcription alter can forces Mechanical receptors transmembrane Mechanosensitive ehnclsgascn hrb,eii hne nthe in 2006). al., changes et elicit Orr Ca as thereby, 2008; such messengers, can, second al., of concentration et signals and Mammoto Mammoto Mechanical 2006; 2009; (Ingber, in can Ingber, cascades complexes modulating (reviewed signaling through adhesion focal nucleus downstream the complexes These in surface changes 2010). transcriptional adhesion trigger Ingber, cell and cell–cell within Mammoto and into signals converted adhesions are biochemical signals plasma mechanical the cytoplasmic Such across 3). forces (Fig. physical membrane transfer and can integrins which as by such cadherins, sensed receptors, preferentially adhesion decades are surface two signals transmembrane past mechanical the that over revealed alter Work has to activity. cytokines factor and hormones transcription soluble the signaling by used intracellular are that harnessing cascades and receptors transmembrane Fg )(hdt ta. 09.I ern,Ca neurons, In 2009). al., et (Thodeti angiogenesis for 3) crucial (Fig. is that additional remodeling cytoskeletal inositol-3-kinase promotes activates phosphatidyl which stimulates (PI3K), in change potential resultant The the 2010). membrane of al., application et the (Matthews force after mechanical mseconds 5 4 member within V channels subfamily (TRPV4) channel cation potential receptor transient aha n tmltsteepeso fgnsta r essential respectively) are that MAPK1, genes and of expression MAPK3 ERK2 the stimulates and as and pathway ERK1 known the also activates (ERK1/2, channels ion mechanosensitive hneso h elsrae nedteilcls cyclic cells, ECM-bound endothelial and In ECM Ca the surface. induces through receptors cell integrin applied strain the ion mechanical mechanosensitive on of activation channels the involves transcription 1993). Izumo, of al., and et Sadoshima Orr 2009; 2004; al., and Martinac, et Mammoto 2008; Papachristou 2002; 2009; al., 2006; Ingber, et al., and Mammoto 2009; et Huang growth, Ingber, 2009; (Alenghat migration, al., remodeling et including Balligand matrix processes, and cellular differentiation MAPKs controlling all in as involved are such virtually which molecules, GTPases, small signaling Rho-family protein and activate or oxide, n ftems ai ehnclsgaigptwy upstream pathways signaling mechanical rapid most the of One ehnsniietasrpin3067 transcription Mechanosensitive P 3 ,daygyeo DG,cM n nitric and cAMP (DAG), diacylglycerol ), 2+ nlxtruhmechanosensitive through influx b nernrcposand receptors integrin 1 2+ 2+ lx inositol flux, lxthrough flux Journal of Cell Science on ihpesr rhii NF- FBXO32 FOS NF- atrophy NF- NF- Muscle Arthritis Osteoporosis AP1 injury lung Ventilator-induced Asthma syndrome pressure pressure bowel Low High Irritable Atherosclerosis pressure Low pressure High pressure High Muscle pressure flow High Turbulent Joint Bone tract Gastrointestinal Lung Lung vessel Blood eso Ca ta. 09 ieiee l,20) ato this of Part 2001). al., et Riveline 2009; al., force , et cytoskeletal regulating and (Chan by mechanical part tension A in mechanotransducers, transmembrane filamin as act paxillin, also mediate , including and (Ingber, transmission, string integrins bow and to bow a of use integrity a the 2006). in resembles mechanotransduction tensional control that to cells, the way released a in and prestress stored of is level through which micromechanical Mechanotransduction this to mechanics 1993). sensitive is (Ingber, and mechanism the (‘tensegrity’) micromechanical balance shape stabilize that turn, of as in cells cell forces, adhesions neighboring result These ECM filaments. to actomyosin a by contacts cytoskeletal a adhesive generated as in as are held well tension which are forces, prestressed isometric contractile tensionally of are that state tissues transcription and of regulator Cells a as cytoskeleton The and lipids of release inositol the in of results which Ca cytoplasm, metabolism the phospholipases in the acid membrane-associated arachidonic increase the activate thereby, of distortion also and, al., and et strain shape Jeon I Mechanical 2010; type 2009). cell al., al., as et et such (Hong Kook bone remodeling, 2009; in and osteopontin formation and tissue collagen that molecules for of crucial expression transcription are upregulate the thereby, are al., activate and, they AP1 signals et where factor JNK Ishida nucleus the and/or 2002; into Ingber, ERK1/2 transmitted and activated Huang Mechanically 2004; 2002; 1996). al., in et al., (Boutahar pathways et adhesions N- D’Addario focal MAPK8) focal in Jun stimulating (FAK) as by kinase and fibroblasts adhesion known and MAPK14) osteoblasts also as cells, endothelial (JNK, known kinase (also terminal MAPK p38 ERK1/2, al., et Wheeler 2001; element al., et responsive 2008). MKL1 (Dolmetsch cAMP References (CREB) factor protein through transcription binding formation the memory of and activation plasticity survival, neuronal for regulation Transcriptional hypertrophy Cardiac conditions volume Pathological and/or pressure High deregulation Mechanical Heart system Organ 3068 htmdlt rncitoa ciiista r rca o cell for mechanosensitive crucial messengers are remodeling. second tissue between that and of These activities differentiation the transcriptional variety interplay 1994). modulate to a that 1991; and al., transmitted an receptors are al., et transmembrane cues through et Tseng mechanical Komuro nucleus that 1993; 1999; suggest Izumo, Lindahl, findings and and Sadoshima (Bishop AP1 and 3) EGR1 as (Fig. activation such factors, through transcription cardiomyocytes mechanosensitive of of remodeling the and (PKC) a oa deinpoen htpyial opeatnfilaments actin couple physically that proteins adhesion Focal the including pathways MAPK activate forces Mechanical 2+ co-activator; , rmitaellrsoe,atvto fpoenkns C kinase protein of activation stores, intracellular from ora fCl cec 2 (13) 125 Science Cell of Journal b rncito factor. transcription , al .Drgltdmcaorncito ndfeetdisease-states different in mechanotranscription Deregulated 1. Table ailnadzxn le hi idn ieisi force- a in kinetics binding their as such alter proteins, adhesion zyxin, focal and some Zhao Moreover, 2007; paxillin al., 2007). et al., the (Mammoto and et tension II cytoskeletal myosin pathway, of sustain of signaling phosphorylation generation control Rho to to the cues back modulate feeds mechanical which forces focal that of These signals translation traction 1997). chemical facilitate into al., also cell et proteins (Ezzell the adhesion resists 3) of (Fig. strength prestress that physical cytoskeletal the adhesion regulating by focal mediated is response ise eg ri smsl sbn)(nlre l,2006). al., actin et tension, (Engler cytoskeletal alter bone) compliance vs ECM muscle when in respective vs the their Changes osteocyte) brain of mirror moduli) (e.g. vs that Young’s tissues stiffnesses the myocyte (i.e. mechanical properties vs with physical cell ECMs neuron tissue-specific on (e.g. cultured undergo switches and fate factors transcription specific 2007). adhesion al., focal et and/or (Morita cytoskeletal by genes of adhesions focal transcription and the fibers stress activating of MKL2 formation and/or Rho- the MKL1 2008). mediates controlling of al., and translocation in et nuclear (Descot role the growth regulates key cell RhoA a and progression Myocardin- expression have gene are 2007). also dependent which cycle respectively), SRF, al., MKL2, of and et (MKL1 co-activators 2 cell Mammoto and 1 2004; proteins like in al., al., et et (Mammoto changes (Mammoto mediates mechanism Rho cell-shape-dependent signaling inactivates distortion-dependent it This 2007). the where to p190RhoGAP fraction moves and RhoGAP By lipid-raft Subsequently, calpain A. protein 2007). by filamin actin-binding cleaved from al., an dissociates is et A, F-actin, (Mammoto filamin crosslinks Rho cells, that spreading of in activation inhibited, contrast, is the p190RhoGAP (GAP) protein to is to activating binds GTPase cytoskeleton leading A a actin as filamin activity the round, its and are When cells 2004). and al., and disrupted et ROCK Mammoto between al., 2007; balance et (Mammoto as cell- the (mDia) formins Diaphanous-related altering known in mammalian by (also changes progression p190RhoGAP cell-shape-dependent of cycle through control mediates activity cytoskeleton-dependent ARHGAP35) Riechmann, GTPase actin and of (Wang example, Rho regulation level the For transcriptional to a 2007). a forces at have mechanical growth to coupling tissue seems in itself gene role cytoskeleton central actin regulate the proteins, to adhesion transcription to act 2003). of Gilmore, can them and they co-activators enables (Wang where expression This nucleus as and 2006). cytoplasm directly al., the et between shuttle (Lele manner dependent ua eecya tmcls(Ss xrs organ- express (MSCs) cells stem mesenchymal Human and signaling various of involvement the to addition In k k k k b b B B B B a b b b b EGR1 , b MURF1 , b b Snr,2008) (Sandri, 2004) al., et (Agarwal 2010) al., et (Bergmann 2001) al., et (Hirokawa 2007) Wang, and (Ning 2003) al., et (Kumar 2000) al., et (Gimbrone 2007) al., et (Zhao Journal of Cell Science lmns hc r novdi ope edaklo:they loop: control feedback complex mechanosensitive a al., in central involved et are are Ren fate which generate cytoskeleton prestress 2004; elements, actin MSC which the al., tensional that Myo-II, on suggest et and further and (Engler shape findings These 3) Rho 2009). cell (Fig. by tension and mediated cytoskeletal compliance is the and ECM 2004), switching al., of et Polte 2003; effects (Ingber, shape cell and structure nopuioetse el hntefre nuto fOCT4, of induction forced the than cells reprogram cells to stem way pluripotent more-efficient that a into is as this such Moreover, 2008). genes ( pluripotent OCT4 silenced is encoding reactivate oocytes or For to eggs into pluripotency. sufficient nuclei somatic of of reprogramming transplantation example, transcriptional for nuclear crucial of the 2007). Shivashankar, al., reorganization and et as and Pajerowski nucleus (Mazumder 2010; stiffer emerge cytoskeleton dynamic a cells cell to lineage-committed leading stem the the progressively because thereby be 3), nuclear membrane, between to also (Fig. might fate connections leads of prestress cell the Nuclear differentiation determine 2007). mechanism and to al., cell ions signaling crucial the et of on propagation a (Li the act than molecules that faster much forces Shivashankar, such is to surface and response Mazumder in Importantly, mechanotransduction 2008; with al., cytoskeleton 2010). et the Shivashankar, Mazumder of and are (Mazumder forces 2007; chromatin nuclei contractile of of forces balances condensation prestressed, size it this becoming the that nucleus linkages; the and so cytoskeletal in whereas surface through results connection integrin cell cells, physical to the nocodazole coupled adherent of 2010). directly with Shivashankar, area of and the dramatic (Mazumder polymerization Thus, size size a nuclear the nuclear in increases actin of fate possibility, results the of inhibition this disruption D, cell in or of cytochalasin decrease blebbistatin directly support during with with that In microfilaments Myo-II transcription cells. mechanosensor of these a inhibition of in the as 1992), parameters determination al., regulation act et same Sims might 2011; modulates that these al., itself et Given by Kihara 2008). nucleus 2010; regulated Chen, al., et al., and are (Khatau (Ruiz et mechanics patterns (McBeath cytoskeletal nuclear tissue 2006), signaling al., and et Rho–ROCK Dike 2004) (Engler 1997; through al., elasticity et ECM contractility (Chen 1999), shape Importantly, cell al., 2010). altering et by apoptosis al., controlled and be differentiation et growth, can between fate (Buxboim of cell control in determination changes transcriptional the fate in the cell roles and architecture 1997b) adhesions crucial and focal al., have substrate, mechanics ECM cytoskeleton, et nuclear the the by in (Maniotis modulated to changes are prestress that fact, adhesion molecular cytoskeletal In in 3). the changes (Fig. in of to and membrane, or transmission response the ECM in for nuclear path chromatin, signals discrete as mechanical the a well provide as and scaffolds filaments to nuclear cytoskeletal integrins, coupled between scaffolds connections is intranuclear cytoskeleton of The control of point mechanical transcription a as nucleus The transcription changes to on response cues in transcription. state gene mechanical functional in their of alter effects and regulation the mediate both neetnl,tesrcueo h ulu loapast be to appears also nucleus the of structure the Interestingly, Pou5f1 Kme l,20;Satede al., et Stadtfeld 2009; al., et (Kim ) mroeei n htcnrlognhmotss ti now fate, is It cell control homeostasis. stem organ mechanosensitive determine control of that that and role transcription that embryogenesis findings of central multiple mechanisms reviewed the have we demonstrate Commentary, this In Conclusions 2009). al., partial et familial (Worman and mechanics, lipodystrophy cardiomyopathy and dilated structure Emery–Dreifuss dystrophy, syndrome, muscular nuclear progeria perturbed Hutchinson–Gilford as diseases by such congenital caused of treat to development are and the that cells for reprogram crucial to be strategies fate also new will understanding cell mechanisms our Furthering these of control tissues. of microenvironment adult the to and to the embryonic sensitive crucial living are modulates are that and nucleus that determination, the activities of transcriptional these environment through micromechanical (Dreuillet transferred 2004). directly al., are et expression Haraguchi that gene 2002; al., alter forces et also any might 2009), molecules al., et yatrn h rnpr ftasrpinfcoso other or factors transcription of transport the altering by 2009). 1992; al., al., et et Wang Sims 1993; 1997b; structure al., al., et et nuclear Maniotis Wang in receptors, 1997a; changes al., these et tension-dependent (Maniotis with in associated result filaments which across cytoskeletal cadherins) nucleus and the the integrins and to (e.g. transmitted receptors and in adhesion surface transmembrane are control cell that the forces transcriptional on mechanical by exerted The on regulated be 2010). pluripotency therefore, al., might, ESCs et of (Li tension effects ESCs cytoskeletal different of survival decreased hence, long-term and, transcriptional and compromises pluripotency nuclei of actin 2011), in transplanted regulation transcriptional in al., destabilizes role Nuclear OCT4 et encoding essential 2006). gene (Miyamoto an the regulatory (Grummt, of has transcriptional reactivation nucleus of also the assembly polymerization in the is modulating complexes it gene 1999) by al., unclear, induces et through (Sotiropoulos or is transcription dynamics nucleus actin gene transcription cytoskeletal regulate in the can changes of actin by nuclear level of that mechanism known the the structure Although at physical 2010). reprogramming al., the et (Kim Pasque which cells 2010; somatic in al., expression et protein KLF4 and MYC SOX2, itrin–a euto yokltldsoto lostimulates also – Ca membrane distortion cells cytoskeletal nuclear tension-dependent endothelial of cells, cytoskeletal result in spreading a as mechanics In – 2009). ECM distortion al., control to et sensitive which (Mammoto be been GATA2, the have 1995; to VEGFR2, of mechanical and of shown translocation expression al., the TFII-I nuclear regulating to by et of factors angiogenesis levels sensitive (Khachigian transcription The 2002). two specifically cells al., fluid et to endothelial also Meiler response in is in PDGFB perturbation al., stress, and et PDGFA (McGee shear encoding fibroblasts genes of in the NF- transport prestress of transport nuclear by Nuclear example, 2011). regulated For is nucleus. MKL1 the into molecules atr n eas hs rtisaedrcl ikdt the to transcription Me linked to and directly (Mejat bind are nesprin emerin, proteins envelope through and these nuclear cytoskeleton A because Because and lamin gene 2003). induces factors as and al., such 1996) et proteins, Cantiello, (Itano and (Prat transcription 3) (Fig. channels ae oehr hs idnssgetta the that suggest findings these together, Taken ehnclfre a lorglt eeepeso directly expression gene regulate also can forces Mechanical ehnsniietasrpin3069 transcription Mechanosensitive k ,wihatvtsepeso of expression activates which B, 2+ nr hog ula ion nuclear through entry ´ a,21;Wang 2010; jat, Journal of Cell Science ha,M,Tefnds .adMdod .M. R. Medford, and P. Theofanidis, M., Ahmad, gra,S,Dshe,J,Ln,P,Vra . omn . vn,C .and H. C. Evans, C., Hofman, A., Verma, P., Long, J., J., Deschner, P. S., Agarwal, Mack, S., McKinney-Freeman, L., P. Wenzel, O., Naveiras, L., Adamo, Reikera and P. L. Kristiansen, P., Ludvigsen, H., Steen, T., G. Aarnes, References months. 12 Defense after release of ABTA. for and PMC Department Foundation in Hearst the Deposited the [grant AHA, Health DE019023], BC074986], of number and [grant Institutes National CA45548 the by numbers supported was work This declare Funding authors The figures. the for interests. Jiang financial A. competing and no Jiang E. thank We regenerative Acknowledgements and engineering as tissue diseases, for various to strategies medicine. for lead new intervention also control as therapeutic might well deeper of of organs transcriptional adult forms a control and new mechanosensitive embryonic homeostasis, the in mechanisms tissue of to and central understanding processes is developmental Because mechanotransduction events. patterning cellular and activities morphogenetic mechanical transcriptional chemical important forming regulate and during cues to within the mechanical interact tissues how dynamically of analyze entire signals to and way variations a ECM and the organs, local endogenous cells, measure of and to properties order forces in methods understand mechanical new this fully require in Advances will to clear. becoming area is control development during organ transcriptional and property tissue of develop material models into and tissues mechanosensitivity existing integrate shape to how necessity size, The organogenesis. specific about of a lack understanding the regarding of comprehensive because successful fully a transcriptional been not has approach abnormal this mechanical correcting normal restoring or by activities. conditions and diseases a treating loading that embryonic control developmental or possibility reversing mechanotranscriptional of defects the the chance tissue our these raise increase will on drives of mechanisms also understanding findings process formation better These This organ scale. mechano-chemical distances. tissue and propagate long that patterning over molecules neighboring ECM signaling of that distortion and signals produce chemical also cells but the Cell- cells, alter by cytoskeleton. the only conveyed the are on not in depend forces prestress nucleus tensile or the generated tension to isometric and of cell level of signal the mechanical through extent the transferred which The with is efficiency mechanics. the or and response structure this in nuclear changes and mediating by or cytoskeletal pathways transcription transcriptional signaling influence in intracellular cytoskeletal changes signals altering behind mechanical intracellular forces These and driving regulation. stresses be can external tension both that clear 3070 nterglto ftevsua elahso oeue1gn xrsinb tumor by expression gene molecule-1 adhesion cell vascular factor-alpha. the necrosis of regulation the in rifamtr cin fmcaia signals. mechanical of actions proinflammatory N. Piesco, C. M. 1131-1135. Yoder, W., M. Lensch, al. M., et in Yoshimoto, A., lengthening Suchy-Dicey, J., leg Gracia-Sancho, during adaptation tissue improves humans. distraction frequency High ept ra fott nier3 rasfo Ss ofar so ESCs, from organs 3D engineer to effort great a Despite 20) imcaia ocspooeebynchaematopoiesis. embryonic promote forces Biomechanical (2009). .Oto.Res. Orthop. J. ora fCl cec 2 (13) 125 Science Cell of Journal 20) oeo Fkpa rncito atr natifamtr and antiinflammatory in factors transcription NF-kappaB of Role (2004). .Bo.Chem. Biol. J. 20 789-792. , 273 4616-4621. , rhii Rheum. Arthritis 19) oeo ciaigprotein-1 activating of Role (1998). 50 3541-3548. , s O. ˚s, Nature (2002). 459 , ubi,A,Iaosa .L n ice,D E. D. Discher, and L. I. Ivanovska, A., Buxboim, omtc,R . avn,U,Ff,K,Sot,J .adGeneg .E. M. Greenberg, and M. J. Spotts, K., Fife, U., Pajvani, E., R. Dolmetsch, rna,B G. B. Bruneau, ie .E,Ce,C . rsc,M,Te,J,Wieie,G .adIge,D E. D. Ingber, and M. G. Whitesides, J., Tien, M., Mrksich, S., C. Chen, E., L. Dike, S. J. Mymryk, and A. F. Dick, L. Lim, and V. V. Kalinichenko, H., R. Costa, othr . ugadn . io .adLfg-rut .H. M. Lafage-Proust, and L. Vico, A., Guignandon, N., Boutahar, G. Lindahl, and E. J. S., Bishop, Goemaere, J., P., J. Alexander, Devogelaer, Y., J., Boutsen, Ren, S., Boonen, M., J., J. McKane, Body, P., K., Bergmann, K. Wen, C., E. Walsh, T., Bartman, epa,N,Spto . oil,P . euear,E n ag,E. Farge, and E. Beaurepaire, A., P. Pouille, W., Supatto, N., Desprat, T., Mercher, A., Menssen, D., Bluteau, Brand, G., Courtois, B., M., C. Rex-Haffner, Phelps, A., E., Descot, A. Christiansen, M., K. Parmar, E., R. G. D. Dawes-Hoang, Harrison, and A. Cutchins, T., Fukai, M., I. Grumbach, E., M. Davis, A. C. McCulloch, and P. R. Ellen, D., P. Arora, E. M., D’Addario, M. Dickinson, and C. J. Culver, N. Wang, and F. Wang, S., T. Tanaka, C., Y. E. Poh, D. D., Ingber, Li, and S., M. Na, G. F., Whitesides, Chowdhury, S., Huang, M., Mrksich, S., C. Chen, M. Goppelt-Struebe, and B. Chaqour, algn,J . eo,O n es,C. Dessy, and O. Feron, L., J. Balligand, L. Schuger, and Y. Zhou, R., K. Badri, A. E. Klein, and K. R. Assoian, E. D. Ingber, and A. Derrien, K., C. Thodeti, D., J. Tytell, J., F. Alenghat, og . edan . un,J,W,S,Zag . oefr,S . Gayyed, A., S. Comerford, N., Zhang, S., Wu, J., Huang, G., Feldmann, J., Dong, amn,C,Ots .C n rn,M. Brand, and C. A. Oates, C., Dahmann, A. C. McCulloch, and P. Bozavikov, D., P. Arora, W., M. Chan, M. Hecker, and I. Eberhardt, M., Cattaruzza, ledo . Bello N., Almendro, R. P. Bennett, and R. Newton, M., D. Slater, C., V. Allport, ic Res. Circ. uigagoeei sn irptendsubstrates. 35 differentiation micropatterned and using apoptosis, angiogenesis growth, between during switching of control Geometric (1999). 894. iaeadpoierc yoiekns yoiestsivle nEKactivation. adhesion ERK in focal involved sites of tyrosine Chem. autophosphorylation 2 Biol. kinase activates tyrosine proline-rich osteoblasts and kinase on strain Mechanical S. Rozenberg, and Y. maintenance. and J. development Reginster, J., Kaufman, Y. zebrafish. D. in development Stainier, cushion and endocardial A. P. Rubenstein, eomto ouae ws xrsint eemn neirmdu differentiation midgut anterior embryos. determine Drosophila to in expression twist modulates deformation expression. gene factor-dependent G. response 6171-6181. Posern, serum and of R. activator Treisman, A., O. Bernard, localization. F. myosin of E. control Wieschaus, H., A. and development. spreading embryonic stress-induced dictate function. cell and development the cells. of stem embryonic properties in differentiation Material (2010). ymcaia load. mechanical by cardiovascular of remodeling chronic to contraction of tissues. regulation short-term from oto ehns nDoohl n mammals. and Drosophila D. Pan, in and mechanism A. Maitra, control A., R. Anders, F., M. ha tesrgltsedteilnti-xd ytaepooe ciiythrough activity promoter synthase binding. nitric-oxide kappaB endothelial factor nuclear regulates stress Shear transcriptional filamin-A. integrin-mediated protein 1 actin-binding beta 47550. the force-induced, regulates mechanical that a circuit in Sp1 and p38 death. and life cell of control Geometric proteins. CTGF/CCN2 and CCN1 alpha- of actin. expression muscle force-induced smooth mediate cooperatively and PIP5KIgamma expression. receptor B endothelin 37003. in involved factors muscle. stiffness. extracellular characterization. functional and Immunol. Structural J. expression. tissue-specific its and promoter C. the by mediated is integrins through signaling cAMP protein. Galphas of heterotrimeric control Mechanical inln otencesb nLtp acu hne-amdlncmlxthrough complex channel-calmodulin calcium pathway. L-type kinase an MAP by the nucleus the to Signaling aneac ntsu development. tissue in maintenance outside ‘feel’ cells do deeply how nucleus: the of in? physics and and forces cytoskeletal P1aerqie o yl-xgns eeepeso nano pteilcell epithelial amnion in expression gene 2 cyclo-oxygenase (WISH). for line required are AP-1 441-448. , 19) lnn ftehmnpaee nohla elahso molecule-1 adhesion cell endothelial platelet human the of Cloning (1996). hso.Rev. Physiol. .Cl Sci. Cell J. rc m hrc Soc. Thorac. Am. Proc. 90 157 279 509-519. , 20) rncitoa euaino etbaecricmorphogenesis. cardiac vertebrate of regulation Transcriptional (2002). o.Hm Reprod. Hum. Mol. 5411-5421. , 30588-30599. , n . is . ate,P,Lna . Corbı C., Langa, P., Lastres, C., Rius, T., ´n, 123 adoac Res. Cardiovasc. 89 .Cl Sci. Cell J. rnsCl Biol. Cell Trends 297-308. , e.Cell Dev. 481-534. , Microcirculation m .Pyil ugCl.Ml Physiol. Mol. Cell. Lung Physiol. J. Am. Science 20) oddgsrlto,cl hp hneadthe and change shape cell gastrulation, Folded (2005). 21) we RAsfrHippo. for DREAMs Sweet (2011). 19) euaino adoaclrclae synthesis collagen cardiovascular of Regulation (1999). Development .Osteoporos. J. .Bo.Chem. Biol. J. .Cl.Biochem. Cell. J. 20) rwhcnrlb nrclua eso and tension intracellular by control Growth (2008). 5 122 4-10. , 6 15 ESJ. FEBS 294 561-565. , a.Rv Genet. Rev. Nat. 21) h fet fhmdnmcfreon force hemodynamic of effects The (2010). 470-477. , 2769-2781. , 20) mrooia rgno iwysmooth airway of origin Embryological (2008). 42 333-339. , 20) ehnclrglto fteCyr61/ the of regulation Mechanical (2006). a.Mater. Nat. 20) NSatvto ypyia forces: physical by activation eNOS (2009). 18 27-44. , Science 20) al ycrilfnto affects function myocardial Early (2004). 17 347-352. , 20) rncito atr nmuelung mouse in factors Transcription (2001). 273 132 164-178. , 20) ehnsniietranscription Mechanosensitive (2001). 20) lcdto fauieslsize- universal a of Elucidation (2007). 2011 279 LSBiol. PLoS 3639-3649. , 20) T-A saderegulated a is OTT-MAL (2008). 4165-4178. , Cell 21) onayfrainand formation Boundary (2011). 276 106 163-168. , 786752. , 9 1425-1428. , nVtoCl.Dv il Anim. Biol. Dev. Cell. Vitro In 529-538. , 12 82-88. , 130 21) odn n skeletal and Loading (2010). .Bo.Chem. Biol. J. 43-55. , .Bo.Chem. Biol. J. 21) arxelasticity, Matrix (2010). 1120-1133. , 2 E129. , 20) Fkpa and NF-kappaB (2000). 20) neato of Interaction (2002). ,A n Bernabe and A. ´, ee Dev. Genes o.Cl.Biol. Cell. Mol. 280 L823-L838. , 20) Tissue (2008). 20) FAK, (2009). 276 277 36999- , 47541- , 25 (2004). (2001). (2004). (1997). (2009). 889- , 28 ´u, J. , Journal of Cell Science aauh,T,Hlsa .M,Ymn,M,Kui,T,Hsiuh,N,Mr,C., Mori, N., Hashiguchi, T., Koujin, G. M., L. Yamane, Dobbs, M., J. and Holaska, E. T., Collins, Haraguchi, M., L. Scavo, R., Ertsey, A., J. Gutierrez, rmt I. Grummt, E. R. Poelmann, and P. B. Hierck, K., Heiden, der Van C., B. Groenendijk, iboe .A,J,Tpe,J . ae,T,Adro,K .adGarcia- and R. K. Anderson, T., Nagel, N., J. Topper, Jr, A., M. Gimbrone, atl,N,Tnue,O,Sooi .adRsoh,H. Ruskoaho, and I. Szokodi, O., Tenhunen, N., Hautala, D. M. Basson, and P. C. Gayer, un,C n gw,R. Ogawa, and C. Huang, Ko R., J. Hove, C. J. Lee, and A. J. Baek, G., J. Kim, J., H. Lee, M., Y. Jeon, Y., S. Hong, H., Higuchi, H., Nakamizo, H., Yoshida, H., Kishikawa, S., Miura, M., S. Hirokawa, F. Veraitch, and E. A. Pelling, C., Mason, D., Hernandez, L., A. Hemsley, Luodonpa H., Tokola, N., N. J. Hautala, Sigger, and D. A. Bocking, R., Harding, K. G. Pavlath, and M. K. Kegley, O., P. Mitchell, B., B. Friday, C. Marquardt, and Jr M., E. Boyle, C., B. Linden, E., J. Foker, rule,C,Tli,J,Kes .adEnutLne M. Ernoult-Lange, and M. Kress, J., Tillit, C., Dreuillet, ungl . eea,A . oal,H,Chn .M n hamn .I. B. Shraiman, and M. S. Cohen, H., Rouault, A., A. Teleman, L., Hufnagel, Y. Fan, and X. Gong, K., Bai, X., Jia, Y., Huang, E. D. Ingber, and S. Huang, J. M. Wallace, and B. S. Hooper, B. S. Hooper, and R. Harding, K. G. Pavlath, and V. Horsley, B., B. Friday, Ro M., S. Simoes, R., Fernandez-Gonzalez, E. Farge, ag,E. Farge, E. D. Discher, and L. H. Sweeney, S., Sen, J., A. Engler, Bo S., Sen, A., M. Griffin, J., A. Engler, zel .M,Glmn,W . ag . aahrm,N n nbr .E. D. Ingber, and N. Parashurama, N., Wang, H., W. Goldmann, M., R. Ezzell, rncitoa erso,i irpe yamses uainta assEmery- causes that mutation missense a by dystrophy. muscular disrupted Dreifuss is Y. repressor, Hiraoka, transcriptional and L. K. Wilson, ehncldseto ouae lelreihla elpeoyi xrsinby expression phenotypic cell epithelial regulation. alveolar transcriptional modulates distention Mechanical 16 h oeo ha teso T1 L2 n O- xrsini h developing model. the in ligation expression venous NOS-3 a and in KLF2, embryos ET-1, chicken (Bethesda) on of stress system shear cardiovascular of role The esis. Carden hsooyadpathology. and physiology mroi cardiogenesis. embryonic M. Gharib, in gene immediate early and kinase cells. protein epithelial intestinal mitogen-activated H. Ishii, and activates H. Saito, pressure H., Suzuki, C., R. Nakatsumi, involvement heart: rat perfused in pathways. binding autocrine/paracrine GATA4 of activates stretch wall ventricular MyoD. and MEF2 activating by differentiation muscle Differentiation skeletal initiates ciaino hAadFKidcsEKmdae sepni xrsinin expression osteopontin ERK-mediated induces 263-272. FAK fibroblasts. ligament periodontal and force-subjected mechanical RhoA of Activation mouse undifferentiated in cells. blebbing stem induce embryonic force nanomechanical delivered Precisely endothelin-1. via H. activity Ruskoaho, binding and O. lungs. Vuolteenaho, fetal from and to flow liquid on tract birth. before differentiation. muscle skeletal of initiation the atresia. for esophageal of spectrum full the for repair 533-541. primary true a of cells. intercalating in tension by regulated are 17 dynamics II Myosin (2009). 265. adoygncdfeetaino a oemro eecya tmcells. stem mesenchymal marrow bone Res. rat Med. of differentiation cardiomyogenic 264. (Erk)-independent. kinase MAP and cytoskeleton-dependent regeneration. development. lung ntemcaimo igsz eemnto nfydevelopment. fly in determination size USA wing Sci. of mechanism the On primordium. A/C. lamin nuclear and MOK2 factor Res. transcription Acids human Nucleic between interaction 19) iclnpooe elsraigb ehnclyculn nern othe to integrins coupling mechanically by spreading cytoskeleton. cell promotes Vinculin (1997). specification. lineage cell stem directs microenvironments. stiff or soft 166 for implications pathological stiffness: E. D. Discher, 191-196. , 736-743. , 877-887. , n.N .Aa.Sci. Acad. Y. N. Ann. a G. ˜a, 21) ehntasuto ndevelopment. in Mechanotransduction (2011). 20) ehnclidcino ws nteDoohl foregut/stomodeal Drosophila the in Twist of induction Mechanical (2003). 104 20) ci n ysna rncito factors. transcription as myosin and Actin (2006). 41 22 se,R . oohr .S,AeeoBlo,G,Fae,S .and E. S. Fraser, G., Acevedo-Bolton, S., A. Forouhar, W., R. ¨ster, .Ap.Physiol. Appl. J. ur Biol. Curr. 20) nrcricfudfre r nesnileieei atrfor factor epigenetic essential an are forces fluid Intracardiac (2003). 497-505. , 3835-3840. , AE J. FASEB x.Cl Res. Cell Exp. 380-389. , 20) nohla yfnto,hmdnmcfre,adatherogen- and forces, hemodynamic dysfunction, Endothelial (2000). 20) ytbsdfeetaeotmlyo usrtswt tissue-like with substrates on optimally differentiate Myotubes (2004). 71 217-227. , ln x.Pamcl Physiol. Pharmacol. Exp. Clin. 30 4634-4642. , elHat n Cytoskeleton and Health Cell 24 13 i.Ds Sci. Dis. Dig. Nature m .Rsi.Cl o.Biol. Mol. Cell Respir. J. Am. 3625-3632. , 20) iceecl yl hcpiti aeG1 htis that G(1) late in checkpoint cycle cell discrete A (2002). 902 el Signal. Cell. 1365-1377. , 231 u.J Biochem. J. Eur. 19) euaino ugepninadln growth lung and expansion lung of Regulation (1996). 21) ehntasuto nbn earand repair bone in Mechanotransduction (2010). 81 230-240. , 20) h fet fmcaia ocso intestinal on forces mechanical of effects The (2009). 20) oeo h hscceia niomn in environment physicochemical the of Role (2006). 14-26. , 209-224. , fuesArch. Pflugers 421 20) mrnbnigt t,adeath-promoting a Btf, to binding Emerin (2004). Circulation 172-177. , ¨a Cell 20) rsueoela nrae GATA4 increases overload Pressure (2001). ,M,Phka . opae,H., Romppanen, J., Puhakka, M., ¨, 46 21 nean .G,Seny .L and L. H. Sweeney, G., C. ¨nnemann, 1993-2003. , pr .C,Etn .adZle,J A. J. Zallen, and S. Eaton, C., J. ¨per, 1237-1244. , 126 .Ap.Physiol. Appl. J. 20) acnui ciiyi required is activity Calcineurin (2000). 103 18) nlec fuprrespiratory upper of Influence (1986). 677-689. , 271 21) feto li ha teson stress shear fluid of Effect (2010). 443 730-735. , 33 1035-1045. , .Cl Biol. Cell J. 362-369. , 3 273-279. , 20) odn fmechanical of Loading (2001). ur o.Dv Biol. Dev. Top. Curr. 23-34. , 21 20) nvv n nvitro in and vivo In (2002). 223-229. , 20) arxelasticity Matrix (2006). o.Cl.Biochem. Cell. Mol. x.Cl Res. Cell Exp. ur pn ee.Dev. Genet. Opin. Curr. 61 19) Development (1997). 149 68-74. , 20) ietleft Direct (2002). 20) Calcineurin (2003). rc al Acad. Natl. Proc. 657-666. , n.Surg. Ann. .Cl Biol. Cell J. Physiology e.Cell Dev. 275 95 (1999). (2007). (2010). (2011). (2007). 243- , 255- , Arch. 226 335 , , li,E . ug . atgio . ohpli .adAsin .K. R. Assoian, and D. Kothapalli, P., Castagnino, Y., Yung, A., E. Klein, ihkw,H,Mua . ohd,H,Hrkw,M,Nkmz,H,Hgci H., Higuchi, H., Nakamizo, M., Hirokawa, H., Yoshida, S., Miura, H., Kishikawa, i,K,Di . e,B,N,K,Za,R,Chn . i,J,Aye .J,J,H., Ji, J., M. Aryee, J., Kim, P., Cahan, R., Zhao, K., Ng, B., Wen, A., Doi, K., Kim, i,J . eatao . u . Arau G., Wu, V., Sebastiano, B., J. Kim, i . hu . ag . hn .E,S,P,Li . un,H,Go . Yang, W., Guo, H., Kuang, X., Lei, P., Su, E. E., D. M. Shin, Ingber, L., and Wang, J., J. Zhou, Karavitis, D., M., Li, P., Salanga, Mericko, S., M., Kumar, Chen, J., C., Pendse, Bertozzi, P., E., T. Sebzda, Lele, T., J. Shin, Q., Yu, S., J. Lee, E. L. Lanyon, T., Bittig, J., T. Widmann, D., Umetsu, J., Ranft, R., Boriek, Farhadifar, and P., K. B. Landsberg, D. Corry, J., Moore, D., Barron, R., Malya, S., Lnu, A., Kumar, htu .B,Km .H,Hl,C . lo,R .adWrz D. Wirtz, J. and Miyake, and J. S. R. Yuba, Y., Bloom, Shimizu, M., M., S. C. Haghparast, T., Hale, Kihara, H., D. Kim, B., S. Khatau, ok .H,Hag .M,Pr,J . i,E . e,J . en .M n Lee, and M. Y. Jeon, S., J. Heo, M., E. Kim, S., J. Park, M., J. Hwang, H., S. Kook, an,T,Tkhsi . sjsw,T,Aioh,W n ihhr,T. Nishihara, and W. Ariyoshi, T., Tsujisawa, T., Takahashi, T., Kanno, hciin .M,Rsik . iboe .A,J n oln,T. Collins, and Jr A., M. Gimbrone, N., Resnick, M., L. Khachigian, ouo . ao,Y,Kia . hbzk,Y,Krbysi . o,E,Takaku, E., Hoh, M., Kurabayashi, Y., Shibazaki, T., Kaida, Y., Katoh, I., Komuro, an . hat,Y,Biz . re,S,Sai,A,Betl .A,Rtebc,R., Rattenbach, A., D. Breitel, A., Sharir, S., Krief, E., Blitz, Y., Shwartz, J., Kahn, lzrv .A. G. Ilizarov, Ko en .M,Ko,S . o,Y . i,E . ak .S,Km .G n Lee, and G. J. Kim, S., S. Park, M., E. Kim, O., Y. Son, H., S. Kook, M., E. Y. Jeon, Ruoslahti, and A. S. Lipton, D., Zhang, S., Okamoto, N., Itano, E. D. Ingber, B. E. D. Kablar, Ingber, and M. Baguma-Nibasheka, R., M. Inanlou, lzrv .A. G. Ilizarov, sia . eesn .E,Kvc,N .adBr,B C. B. Berk, and L. N. Kovach, E., T. Peterson, T., Ishida, E. D. Ingber, lc,V,Shr . enne-alse,G . ern,L n etn M. Leptin, and L. Serrano, J., G. Fernandez-Ballester, T., Seher, V., ¨lsch, 86-91. dci . aasm,R . uui . at,H tal. et H. Saito, cells. epithelial H., intestinal Suzuki, by secretion C., IL-6 induces R. pressure Nakatsumi, M., Adachi, hlc,L .e al. et Nature I. L. Ehrlich, . uu . hih . a e om .e al. et D. Boom, den van cells. M., stem neural Ehrich, adult in D., pluripotency Ruau, K., utfctdhmnebyncse elfunctions. cell stem embryonic human al. multifaceted et L. of Cheng, adhesions H., focal within kinetics unbinding zyxin cells. alter living forces Mechanical (2006). al. vivo. et in L. forces hemodynamic Cheng, vascular D., Zhou, M., Stadtfeld, Res. Miner. boundary. compartment anteroposterior Drosophila 1950-1955. the at sorting cell Ju A., Said, asthma. in implications parenchyma: lung in J. kinases FASEB protein mitogen-activated and M. A. rpriso eecya tmclsaecodntdb h eiula ci cap. actin perinuclear the by coordinated Commun. are Res. cells Biophys. Biochem. stem mesenchymal of properties disease. and health in cap actin perinuclear eidna iaetfbolsstruhatvto fEKJKadAP-1. and ERK/JNK of activation Biochem. through fibroblasts ligament periodontal C. J. ha-tesrsos lmn nvsua nohla el xoe ofudshear fluid to exposed cells endothelial vascular B-chain factor in stress. growth element platelet-derived response the with shear-stress functionally interacts B factor-kappa pcfcgn xrsini utrdrtcricmoye.Psil oeo protein of role Possible myocytes. cardiac rat activation. cultured C in kinase expression Y. gene specific Yazaki, and F. ehnclsrs-eitdRn2atvto sdpneto a/R12MAPK Ras/ERK1/2 on dependent osteoblasts. is in activation signaling Runx2 stress-mediated Mechanical fate. cell al. progenitor et joint B. maintain R. to Rountree, P., Maire, F., Relaix, 52. atI h nlec fsaiiyo iainadsf-isepreservation. soft-tissue and fixation of Res stability Relat. of influence The I. Part RhoGEF2. of Control olgnadotootni ua igvlfibroblasts. gingival human in osteopontin and collagen C. regulation J. gene physical nucleus. a the to calcium: surface 5186. nuclear cell the and from pathway endoplasmic controls spreading atI.Teifuneo h aeadfeunyo distraction. of frequency and rate the of Res influence The II. Part dein ellrtnin n elccecontrol. cycle cell and tension, cellular adhesion, ciainb lwi nohla el.Rl fbt nern n yoiekinases. tyrosine and integrins 1 beta of Role cells. Res. endothelial Circ. in flow by activation again. globally. cytoskeleton. the govern organogenesis. lung in movements breathing-like 29,263-285. (239), . 20) oeo AKi ehnclfreidcdu-euaino yeI type of up-regulation force-induced mechanical in MAPK of Role (2009). 20) ehnclsrthatvtsncerfco-apB ciao protein-1, activator factor-kappaB, nuclear activates stretch Mechanical (2003). AE J. FASEB .Ci.Invest. Clin. J. 20) ehnclfreidcstp olgnepeso nhuman in expression collagen I type induces force Mechanical (2009). 467 rc al cd c.USA Sci. Acad. Natl. Proc. 106 28,249-281. (238), . 17 79 lce,F n amn,C. Dahmann, and F. ¨licher, 285-290. , Science Drosophila 19) ellrtnert:dfnn e ue fbooia einthat design biological of rules new defining tensegrity: Cellular (1993). 20) ehnsnaintruhitgis el c oal u think but locally act cells integrins: through Mechanosensation (2003). up.2 Suppl. 7 .Cl.Physiol. Cell. J. 19) oto fbn rhtcueb ucinlla bearing. load functional by architecture bone of Control (1992). 20) ellrmcaorndcin utn l h icstogether pieces the all putting mechanotransduction: Cellular (2006). 1800-1811. , 310-316. , 18b.Tetninsrs feto h eei n rwho tissues. of growth and genesis the on effect tension-stress The (1989b). 18a.Tetninsrs feto h eei n rwho tissues: of growth and genesis the on effect tension-stress The (1989a). 1060-1067. , 20 ehnsniietasrpin3071 transcription Mechanosensitive 315 811-827. , .Bo.Chem. Biol. J. 21) nertdbohmcladmcaia inl regulate signals mechanical and biochemical Integrated (2010). 21) pgntcmmr nidcdpuioetse cells. stem pluripotent induced in memory Epigenetic (2010). 19) ehncllaigsiuae elhprrpyand hypertrophy cell stimulates loading Mechanical (1991). 96 S369-S375. , 384-386. , atuainb pcllclzto fahrn ucin and junctions adherens of localization apical by gastrulation .Cl.Biochem. Cell. J. 1169-1175. , .Cl Sci. Cell J. 207 187-194. , 409 266 104 100 e.Cell Dev. 1-6. , z-rv,M . as,P,Gnie . Ko, L., Gentile, P., Sasse, J., M. ´zo-Bravo, e.Cell Dev. 1265-1268. , Cell 613-627. , 1472-1474. , 20) nrae elbn eso governs tension bond cell Increased (2009). 101 20) l2i nesnilrgltrof regulator essential an is Klf2 (2006). Nucleus 136 20) ucecnrcini necessary is contraction Muscle (2009). rc al cd c.USA Sci. Acad. Natl. Proc. 1266-1277. , 16 411-419. , 11 itl Histopathol. Histol. ehd Enzymol. Methods 734-743. , 845-857. , .Cl Biol. Cell J. 1 337-342. , o.Cl.Biochem. Cell. Mol. 20) h oeo fetal of role The (2005). ln x.Immunol. Exp. Clin. 20) Oct4-induced (2009). 19) A kinase MAP (1996). ln rhp Relat. Orthop. Clin. 20) Transmural (2002). 191 21) Physical (2011). 19) Nuclear (1995). 631-644. , 426 20 ur Biol. Curr. ln Orthop. Clin. 1261-1266. , 20) Cell (2003). 21) The (2010). 20) Cell (2007). 155-175. , 100 320 .Bone J. .Cell. J. (2007). (2007). 5181- , 45- , 129 19 , , Journal of Cell Science io,P. Minoo, T., R. C. Matsui, Mendelson, L., Li, J., Gianetti, Me E., R. Gerszten, R., R. Hung, E., S. Meiler, E. Dzierzak, and A. Medvinsky, atn . adrli .M,Pry .C,Fls .A n ob .R. B. R. Martinac, Cobb, and A. K. Felts, C., G. Parry, M., P. Cardarelli, T., F. Martin, E. Wieschaus, and M. Kaschube, C., A. Martin, ce,K . atann .K,Ka,P . rimn .adBil,M. Bailly, and R. Treisman, T., P. Khaw, K., M. Vartiainen, M., K. McGee, K. K. Parker, and L. M. McCain, aits .J,Ce,C .adIge,D E. D. Ingber, and S. C. Chen, J., A. Maniotis, E. D. R., Ingber, and Derda, K. Bojanowski, A., J., A. Gibbs, Maniotis, T., Tat, S., Y. Torisawa, A., Mammoto, T., E. Mammoto, D. Ingber, and T. Mammoto, E. D. Ingber, and T. Mammoto, A., Mammoto, E. D. Ingber, and S. Huang, A., Mammoto, E. D. Ingber, and P. Oh, K., Moore, S., Huang, A., Mammoto, cet,R,Prn,D . esn .M,Barrj,K n hn .S. C. Chen, and K. Bhadriraju, M., C. Nelson, M., D. Pirone, R., McBeath, V. G. Shivashankar, and L. Mahadevan, A., Basu, T., Roopa, A., Mazumder, V. G. Shivashankar, and A. Mazumder, V. G. and Shivashankar, R. D. and Overby, A. A., Mammoto, Mazumder, D., J. Tytell, K., C. Thodeti, D., B. Matthews, amt,A,Cno,K . amt,T,Yn,C . u,D,Aderman, D., Huh, W., C. Yung, T., Mammoto, M., K. Connor, A., Mammoto, E. D. Ingber, and A. Mammoto, atia . atl,N,Prds . oh . ulenh,O,Nmr .and M. Nemer, O., Vuolteenaho, M., Toth, P., Paradis, N., Hautala, M., Marttila, ak .P n wn,G K. G. Owens, and P. C. Mack, C. Bonifer, and R. Ingram, H., Krysinska, Z. M., Hoogenkamp, Zhao, M., and Lichtinger, S. Luo, L., Zheng, G., Chen, J., Li, 3072 ode .A,Nue,H . eg .M,L,X,L,C,Toz,C,Zu .and N. Zhu, C., Tiozzo, C., Li, X., Li, M., J. Jeng, T., H. Nguyen, A., V. Londhe, jt .adMsei T. Misteli, and A. ´jat, specificity. expression. gene protein surfactant 52. conditions. flow laminar 34 under adhesion monocyte A. for Rosenzweig, required and Jr, A., M. Gimbrone, region. AGM the by initiated tion. AP-1. and B NF-kappa of action cooperative human the Immunol. in on expression depends gene cells protein-1 endothelial chemoattractant monocyte of induction Cytokine ula rnpr ftesrmrsos atrcatvtrMT- sdownregulated is MRTF-A homeostasis. coactivator factor tensional response at serum the of transport function. Nuclear cardiac on architecture cytoskeletal and Arch. shape, myocyte stress, ci-ysnntokdieaia constriction. apical drive network actin-myosin stabilize that nucleoplasm and structure. filaments, nuclear cytoskeletal integrins, between connections cells. living Biochem. from removed Cell. genomes J. intact within disassembly reversible formation. organ tooth al. embryonic et and D. condensation Huh, Cell W., mesenchymal C. of Yung, M., control Bruijn, de R., Mannix, p190RhoGAP of accumulation rafts. controlling lipid by in regulation Rho to structure cytoskeletal and pathway Skp2-p27kip1 the of control transition. shape-dependent G1/S cell the in ROCK and mDia, elsae yokltltnin n hArglt tmcl ieg commitment. lineage cell stem a regulate RhoA of Cell and Dev. tension, integrity cytoskeletal structural shape, Cell the reveals decondensation nucleus. prestressed chromatin mechanically of Dynamics development. 3 and differentiation cellular during architecture nucleus nuclear of aspects unusual cells. reveals living assembly within chromatin of perturbation integrins. beta1 surface cell to applied forces E. D. Ingber, .M,Msolvk,G,Sih .E n nbr .E. D. Ingber, and angiogenesis. E. controls L. that Smith, mechanism G., transcriptional Mostoslavsky, mechanosensitive M., C. development. vascular of control switching. development. 457 eeepeso nrsos ohmdnmcstress. hemodynamic to response in expression gene H. Ruskoaho, xrsini ioi eedn nCr lmnswti h 5 the within elements CArG on dependent regions. is promoter vivo in expression RUNX1. by regulation Chromatin e.Dyn. Dev. P. Minoo, levels. physiological at stress compressive to Biochem. response in modulation S321-S330. , 349-359. , 1103-1108. , 21 .Cl Sci. Cell J. 462 758-769. , 20) rncitoa euaino ugdvlpet mrec of emergence development: lung of regulation Transcriptional (2000). 89-104. , 304 27 6 ora fCl cec 2 (13) 125 Science Cell of Journal 20) Fk nue ugmtrto uigmueln morphogenesis. lung mouse during maturation lung induces NF-kB (2008). 237 ur pn elBiol. Cell Opin. Curr. 483-495. , epr Res. Respir. 20) ehnsniieincanl:mlclso mechanotransduc- of molecules channels: ion Mechanosensitive (2004). 1091-1097. , 45-52. , .Cl Sci. Cell J. Development 328-338. , 21) lr-ai ciaino RV o hnesb mechanical by channels ion TRPV4 of activation Ultra-rapid (2010). 20) AA eitsatvto fteBtp aruei peptide natriuretic B-type the of activation mediates GATA4 (2001). 20) oeo rncito atr nftlln eeomn and development lung fetal in factors transcription of Role (2000). 117 rc al cd c.USA Sci. Acad. Natl. Proc. 65 ic Res. Circ. ipy.J. Biophys. .Bo.Chem. Biol. J. 114-130. , 2449-2460. , 21) ICcmlxsi elhaddisease. and health in complexes LINC (2010). 1 109-115. , MORep. EMBO 120 137 84 456-467. , Cell 93 1407-1420. , 852-861. , 20) yokltlcnrlo rwhadcl fate cell and growth of control Cytoskeletal (2009). 21) ehntasuto:terl fmechanical of role the Mechanotransduction: (2011). 19) euaino mohmsl alpha-actin muscle smooth of Regulation (1999). 19) eiiiehmtpissi autonomously is hematopoiesis Definitive (1996). ur pn Hematol. Opin. Curr. 2209-2216. , 21 ipy.J. Biophys. 21) ehnclcnrlo iseadorgan and tissue of control Mechanical (2010). lo el o.Dis. Mol. Cells Blood 86 279 nu e.Physiol. Rev. Annu. 864-870. , 897-906. , 12 21) mrec fapetesdeukaryotic prestressed a of Emergence (2010). 26323-26330. , 963-970. , 20) odnnpril-sitdlaser Gold-nanoparticle-assisted (2007). 20) nohla K easgaigis signaling beta IKK Endothelial (2002). ner il (Camb) Biol. Integr. 19b.Dmntaino mechanical of Demonstration (1997b). 94 95 20) iai ik elsaeand shape cell links Filamin (2007). 20) h inln n mechanical and signaling Rho (2008). Nature 849-854. , 3028-3035. , 19a.Mcaia otniyand continuity Mechanical (1997a). 20) usdcnrcin fan of contractions Pulsed (2009). Endocrinology 20) sebatcytoskeletal Osteoblast (2007). 457 15 62 .R o.Interface Soc. R. J. 44 228-234. , 21) Mechanochemical (2011). 875-915. , 495-499. , 287-290. , 20) oeo RhoA, of Role (2004). .Ml el Cardiol. Cell. Mol. J. 9 2 142 435-442. , n is intron first and Nucleus 4693-4700. , 20) A (2009). o.Cell. Mol. Suppl. 7 Pflugers (1997). (2011). (2004). (2008). (2010). Nature u.J. Eur. 1 Dev. 40- , or,K . un,S,Kn,Y,Sna,M .adIge,D E. D. Ingber, and E. M. Sunday, Y., Kong, S., Huang, A., K. Moore, oir . eise-oir . rn,A .adSno,B. Sanson, and H. A. Brand, A., Pelissier-Monier, B., Monier, aahitu .J,Ppcrn,K . ada .K n aaaslo,A G. A. Papavassiliou, and K. E. Basdra, K., K. Papachroni, J., D. Papachristou, iaoo . aqe . ule,J n udn .B. J. Gurdon, and J. Jullien, V., Pasque, K., Miyamoto, aeosi .D,Dh,K . hn,F . amk .J n ice,D E. D. Discher, and J. P. Sammak, L., F. Zhong, N., A. K. Dahl, M. D., Schwartz, J. Pajerowski, and R. B. Blackman, P., and B. J. Helmke, I. W., Sarembock, A. E., Orr, Coleman, M., Bevard, M., J. Sanders, W., A. Orr, ac,C,Bue,A . eel,J n ag,E. Farge, and J. Deleule, C., A. Brunet, C., Rauch, E. Farge, and C. A. Brunet, P., Ahmadi, A., P. E. Pouille, D. Ingber, and N. Wang, S., G. Eichler, R., T. Polte, zw,N,Sihr,M,Iahn,M,Fki . ohmt,T n iaa Y. Hirata, and T. Yoshimoto, N., Fukai, M., Iwashina, M., Shichiri, N., Ozawa, D. K. Irvine, and H. Oh, D. K. Irvine, and H. Oh, abCle,D . hee .A,Ptre,D . iml .B n Recker, and B. D. Kimmel, N., D. Petersen, A., M. Thiede, M., D. Raab-Cullen, F. H. Cantiello, and G. A. Prat, Kumacheva, A., Nagy, A., G. Wood, T., Yin, C., Bauwens, M., B. Rao, R., Peerani, B. J. Gurdon, and K. Miyamoto, V., Pasque, uak,R . uhi,P . rnly .M,Yl,F .adKr,L D. L. Kerr, and E. F. Yull, M., D. Brantley, B., P. Bushdid, S., R. Muraoka, Oxburgh, C., A. Mackinnon, T., W. Pu, A., M. Peterson, J., Wang, P., I. Moskowitz, K. Sobue, and T. Mayanagi, T., Morita, ot,T . osln,W,Pees . i . el . od .M,Wbr .J., G. Weber, M., A. Lord, C., Ceol, P., Li, M., Peeters, W., Goessling, E., T. North, asn,S . ily .P,Wlis .J,Beo .F,Tia .L,Nisn .R., J. Neilson, L., C. G. Tsika, J. F., O. Dunn, Bueno, J., and B. Wilkins, B. P., D. J. Millay, A., Atkinson, S. Parsons, M., B. Wu, P., D. Puapong, J., Park, ig .M n ag .R. X. Wang, and and M. A. A. Q. Spector, Ning, J., N. Sniadecki, F., W. Liu, L., J. Tan, P., R. Jean, M., C. Nelson, Ives, and J. Holtz, P., V. Sukhatme, E., Wilson, F., Vives, H., Y. Ma, H., Ingber, Morawietz, and E. M. Sunday, E., Alsberg, B., Shi, S., Huang, T., Polte, A., K. Moore, coysnbsdbririhbt elmxn tcmatetlbudre in boundaries compartmental at mixing cell embryos. inhibits Drosophila barrier actomyosin-based oyeiaini eurdfrtasrpinlrpormigo c4b oocytes. by Oct4 of reprogramming transcriptional Dev. for Genes required is polymerization 20) hsclpatct ftencesi tmcl differentiation. cell stem in nucleus the USA Sci. of Acad. plasticity Physical (2007). atherosclerosis. in role potential a 202. flow: by activation kappaB A. M. Schwartz, rndfeetainsesehne yeieei niiino M2endocytosis. BMP2 of Physiol. inhibition Cell Physiol. epigenetic J. by Am. enhanced steps transdifferentiation 20) aia ha tesu-euae nuil ircoiesnhs nthe in synthase oxide nitric inducible up-regulates stress endothelium. shear Laminar (2004). mechanotransduction. of Mechanisms Oncogene expression. R. R. embryos. Drosophila in invagination mesoderm Signal. and Sci. redistribution II Myosin trigger modulation prestress. through cytoskeletal and contractility shape cell cell and of phosphorylation chain light myosin controls differentiation. and self-renewal W. cell P. Zandstra, and E. reprogramming. nuclear ee md n aa oprtvl r cooperatively al. Gata4 et L. and Smoot, [corrected]. C., Smad4 Berul, M., Sarkar, genes C., G. Chu, L., by genes adhesion (MRTFs/MAL/MKLs). 3432-3445. cytoskeletal/focal factors of transcription regulation myocardin-related transcriptional via cytoskeleton ars . utn,C . un,P tal. et localization. P. flow. Huang, blood C., on dependent C. is development Cutting, J., Harris, ci filaments. actin al. et W. R. Tsika, fiber hypertrophy. muscle not R., skeletal but G. overload-induced switching mechanical Crabtree, type blocks E., calcineurin of K. loss Yutzey, Genetic M., C. Liberatore, mechanics. and S. C. growth Chen, epithelial lung. inhibits chick embryonic factor-kappaB the nuclear in branching of expression Mesenchymal cells. muscle smooth vascular in strain E. H. tension. cytoskeletal and Rho by 268-281. lung embryonic in morphogenesis E. D. n ula atrkpa ymcaia tec euti etlto-nue lung ventilation-induced in result stretch mechanical by injury. factor-kappaB nuclear and neoeei ymcaia eghnn:mrhlg n ucino h lengthened the of intestine. function and small morphology lengthening: mechanical by Enterogenesis mechanotransduction regulating factors bone. transcription in and networks Signaling (2009). febyncln rnhn opoeei yteRoatvtr cytotoxic activator, Rho the by morphogenesis branching 1. factor lung necrotizing embryonic of 19) ai nuto n rnlcto fEr1i epnet mechanical to response in Egr-1 of translocation and induction Rapid (1999). 20) oto fbsmn ebaermdln n pteilbranching epithelial and remodeling membrane basement of Control (2005). e.Hypotheses Med. 19) ehncllaigsiuae ai hne nprota gene periosteal in changes rapid stimulates loading Mechanical (1994). Bioessays 28 rc al cd c.USA Sci. Acad. Natl. Proc. acf iseInt. Tissue Calcif. 2 rc al cd c.USA Sci. Acad. Natl. Proc. 20) mretpten fgot otoldb utclua omand form multicellular by controlled growth of patterns Emergent (2005). 25 Development 1916-1927. , ra16. , yetn.Res. Hypertens. 946-958. , .Pdar Surg. Pediatr. J. m .Physiol. J. Am. 104 20) h uedteiletaellrmti ouae NF- modulates matrix extracellular subendothelial The (2005). 31 15619-15624. , .Sr.Res. Surg. J. a.Cl Biol. Cell Nat. 794-804. , odSrn ab yp un.Biol. Quant. Symp. Harb. Spring Cold 68 20) nvv euaino okepopoyainand phosphorylation Yorkie of regulation vivo In (2008). 20) ih-eitdcnrlo ua mroi stem embryonic human of control Niche-mediated (2007). 20) nvv nlsso okepopoyainsites. phosphorylation Yorkie of analysis vivo In (2009). 135 356-360. , 20) ciain fmtgnatvtdpoenkinase protein mitogen-activated of Activations (2007). 283 27 1081-1088. , 55 19) ula o hne ciiyi euae by regulated is activity channel ion Nuclear (1996). 270 93-99. , 473-478. , 39 C235-C243. , 104 1823-1827. , C1532-C1543. , .Bo.Chem. Biol. J. 12 MOJ. EMBO 95-100. , e.Cell Dev. m .Pyil elPhysiol. Cell Physiol. J. Am. 60-65; , ic Res. Circ. 102 108 e.Biol. Dev. Cell 11594-11599. , 4006-4011. , 21) fiinisadmcaim of mechanisms and Efficiencies (2010). glt ada va cardiac egulate 20) eraiaino h actin the of Reorganization (2007). 26 137 Suppl. 10 20) 21 myoblast/osteoblast C2C12 (2002). 4744-4755. , 84 20) eaooei tmcell stem Hematopoietic (2009). 736-748. , 11-20. , 225 279 678-687. , 322-338. , 26192-26200. , 1-9. 20) xrclua matrix Extracellular (2004). 21) rncito factor Transcription (2011). 20) ehnclsignals Mechanical (2009). 21) ula actin Nuclear (2011). .Cl Biol. Cell J. 75 x.Cl Res. Cell Exp. v development. lve 189-200. , 286 e.Dyn. Dev. 20) Control (2002). C518-C528. , 21) An (2010). rc Natl. Proc. 169 (2006). (2004). (2000). (2004). 191- , 313 232 , , Journal of Cell Science ee,T . aaih,M,Vglag .adLpi,M. Leptin, and E. Vogelsang, M., Narasimha, C., T. Seher, hu .T,Wis .A,Hyn,J . wmt,M . on,I .adQa,C T. I. C. Quam, B. and Shraiman, S. I. Joung, N., M. Iwamoto, B., J. Hoying, A., J. Weiss, T., Y. Shiu, K. Basler, and G. Schwank, S. Izumo, and J. Sadoshima, S. C. Chen, and A. S. Ruiz, P. P. Tam, and J. Rossant, ibl,J G. J. Tidball, R. Treisman, and J. Copeland, D., Gineitis, A., Sotiropoulos, asrsGri,L,Bsut . aa . oeua . a,C,Ssk,H and H. Sasaki, C., Tao, S., Yonemura, K., Wada, W., Bossuyt, L., Sansores-Garcia, M. Sandri, E. L. Lanyon, and H. T. C. C. Rubin, Turner, and B. A. Castillo, G., A. Robling, hdt,C . ates . ai . amt,A,Goh . rca .L and L. A. Bracha, K., Ghosh, A., Mammoto, A., Ravi, B., Matthews, K., C. K. Thodeti, Hochedlinger, and T. D. Breault, N., Maherali, M., Stadtfeld, M. Levine, and A. Blair, S., Small, e,Y,Efe,J . osrm . u,T,Fre,R . geis .A,Rc,R S. R. Rock, A., P. Iglesias, A., R. Firtel, T., Luo, M., Norstrom, C., J. Effler, Y., Ren, J. Jiang, and L. Zhang, F., Ren, K. B. Ray, and A. Shakya, A., Ray, ieie . ai,E,Blbn .Q,Shaz .S,Ihzk,T,Nrmy,S., Narumiya, T., Ishizaki, S., U. Schwarz, Q., N. Balaban, E., Zamir, D., Riveline, is .R,Kr,S n nbr .E. D. Ingber, and S. Karp, R., J. Sims, enc,N,Clis . tisn . otrn .T,Dwy .F,J and Jr F., C. Dewey, T., D. Bonthron, W., Atkinson, T., Collins, N., Resnick, 20) h oeo ehnclsrse nangiogenesis. in stresses mechanical 431-510. of role The in (2005). morphogenesis mesoderm early controlling cascade genetic the the of reconstitution gradients. rc al cd c.USA Sci. Acad. Natl. Proc. pathway. Hippo the affecting G. Halder, myocytes. cardiac of hypertrophy structures. multicellular within magnitude. mouse. the in patterning axis and asymmetries remodeling. bone of regulation molecular adaptation. signaling. integrin-to-integrin through reorientation E. D. mouse. Ingber, in reprogramming cell iPS to Cell fibroblast Stem during cornerstones molecular dynamics. actin in changes by mediated is 159-169. factor response serum of activation embryo. Drosophila 23 D. mechanism. focal ROCK-independent of A. and growth mDia1-dependent Bershadsky, induces 153 an force and by mechanical local contacts B. applied externally Geiger, mechanosensors: Z., Kam, I. cortexillin crosslinker actin the and II N. myosin D. between Robinson, mechanisms. independent and and dependent 14-3-3 Biol. through Dev. activity and localization aac eut nitgae hne ncl,ctseea n ula shape. nuclear and cytoskeletal cell, in changes Sci. integrated in results balance otisacsatn li ha-tesrsosv element. 90 shear-stress-responsive fluid Jr cis-acting a contains A., M. Gimbrone, 1428. expression. gene MMP-1 canine promote Acta c-Jun/c-Fos Biophys. and SAF-1 factors 160-170. , 4591-4595. , 1175-1186. , rspiaembryo Drosophila 103 1215-1222. , 20) inln nmsl toh n hypertrophy. and atrophy muscle in Signaling (2008). odSrn ab eset Biol. Perspect. Harb. Spring Cold 2 337 .Ap.Physiol. Appl. J. 230-240. , acf iseInt. Tissue Calcif. 20) ehnclsga rndcini kltlmsl rwhand growth muscle skeletal in transduction signal Mechanical (2005). 21) ouaigFatnognzto nue ra rwhby growth organ induces organization F-actin Modulating (2011). 20) RV hnesmdaecci tanidcdedteilcell endothelial strain-induced cyclic mediate channels TRPV4 (2009). 20) ehnclfebc sapsil euao ftsu growth. tissue of regulator possible a as feedback Mechanical (2005). 303-312. , 1732 53-61. , MOJ. EMBO . eh Dev. Mech. 20) ehnsnigtruhcoeaieinteractions cooperative through Mechanosensing (2009). 19) ltltdrvdgot atrBcanpromoter chain B factor growth Platelet-derived (1993). 20) mrec fptendse eldifferentiation cell stem patterned of Emergence (2008). 102 20) lsoytlnaefrain al embryonic early formation, lineage Blastocyst (2009). 98 MOJ. EMBO 21) euaino ra rwhb morphogen by growth organ of Regulation (2010). 37 11 18) euaino oems ymcaia strain mechanical by mass bone of Regulation (1985). tmCells Stem 1900-1908. , 3318-3323. , 411-417. , 19) ehntasuto nstretch-induced in Mechanotransduction (1993). 4047-4057. , 21) ip inln euae okenuclear Yorkie regulates signaling Hippo (2010). .Rcp.Res. Recept. J. 19) euaino vnsipdsrp nthe in 2 stripe even-skipped of Regulation (1992). 124 20) nlmainrsosv transcription Inflammation-responsive (2005). 19) leigteclua ehnclforce mechanical cellular the Altering (1992). 30 167-179. , nu e.Boe.Eng. Biomed. Rev. Annu. 2325-2335. , 26 2921-2927. , 2 a001669. , Development 13 ic Res. Circ. 777-794. , 20) oa otcsas contacts Focal (2001). 20) imcaia and Biomechanical (2006). rt e.Boe.Eng. Biomed. Rev. Crit. rc al cd c.USA Sci. Acad. Natl. Proc. 19) Signal-regulated (1999). 136 ur Biol. Curr. hsooy(Bethesda) Physiology 104 20) nlssand Analysis (2007). 701-713. , 1123-1130. , 20) Defining (2008). 8 455-498. , .Cl Biol. Cell J. 19 Biochim. Cell 1421- , .Cell J. Cell 33 98 , , ag . aijwk,B . e,N,Slet . cngt .L,Fags .A. J. Frangos, L., N. McKnight, O., Silbert, N., Lee, S., B. Maciejewski, Y., Wang, V. Riechmann, and Y. Wang, ag .adGloe .D. T. Gilmore, and Y. Wang, E. D. Ingber, and D. J. Tytell, N., Wang, io,P . ada .K n aaaslo,A G. A. Papavassiliou, and K. E. Basdra, G., P. Ziros, Sza P., Arora, C., Laschinger, H., X. Zhao, ag . ulr .P n nbr .E. D. Ingber, and P. J. Butler, N., Wang, ho . i . e,Q n un .L. K. Guan, and Q. Lei, L. L., Li, Schuger, B., and Zhao, I. Ariel, P., Kemp, S., H. Beqaj, Y., J. Yang, Wang, and J. H. Im, G., Yang, io,G .adLgis .C. G. Liggins, and A. G. Vilos, u . esn .M,Mshe,J . esh . odrar .K n Bissell, and K. B. Vonderhaar, M., Veiseh, L., J. Muschler, M., C. Nelson, R., Xu, emt . oohr .S,Leln,M,W,D,Pumr . hrb .and M. Gharib, D., Plummer, D., Wu, M., Liebling, S., A. J. Forouhar, Gille, J., and Vermot, S. Dimmeler, R., Kaufmann, K., Reisinger, M., Stein, C., Urbich, ona,M .adCe,C S. C. Chen, and A. G. M. S. Young, Wozniak, and A. Muchir, G., L. Fong, J., H. Worman, zm,E,IaiThai . ise,W . eaa . cut,D . Engelhardt, A., D. Schultz, E., Dejana, B., W. Kiosses, M., Irani-Tehrani, E., Tzima, K. A. Verma, and R. Kumar, J., Y. Kim, P., C. Tseng, hee,D . art,C . rt,R . aa .adTin .W. R. Tsien, and P. Safa, D., R. Groth, F., C. Barrett, G., D. Wheeler, opr,L. E. K. Wolpert, A. Yutzey, A. and Hislop, E. E. and Wirrig, R. Desai, S., J. Wigglesworth, n ace-sea,J. Sanchez-Esteban, and oogenesis. Drosophila during growth tissue of coordination lqeLMdmi rtisg nuclear. go proteins domain LIM plaque nucleus. the with matrix Biol. extracellular the coupling mechanically ufc n hog h cytoskeleton. the through and surface stretch. Rho the through activity promoter pathway. alpha-actin signaling muscle smooth activates Force (2007). version. updated an tumorigenesis: and control size in production PGE2 and expression, fibroblasts. tendon MMP-1 patellar COX-2, human induced IL-1beta modulates Physiol. lentv piigo eu epnefco rmtsbocilmoeei n is and myogenesis bronchial promotes hypoplasia. lung factor in response defective serum of splicing alternative function. mammary-specific of maintenance and J. M. avlgnssi h eeoigheart. developing the in valvulogenesis E. binding. S. DNA Fraser, Sp1-dependent requires gene receptor-2 transc Lett. FEBS factor stress-induced growth shear endothelial Fluid (2003). rwn oefrcontractility. for role growing therapy. to biology cell basic from trip strange long the htmdae h nohla elrsos ofudserstress. shear fluid to response cell A. endothelial M. the Schwartz, mediates and that H. DeLisser, G., Cao, B., differentiation. disease. and development nuil ee ouae yA- rnnA- rnatn factors. transacting non-AP-1 12-O-tetradecanoylphorbol-13-acetate- or of AP-1 15 by regulation modulated transcriptional genes the inducible in C kinase aKIlclyecdsLtp hne ciiyt inlt ula RBin CREB nuclear to signal to activity channel L-type encodes locally CaMKII pathway. signaling Physiol. Mol. cAMP-PKA-dependent Cell. via Lung Physiol. mediated is differentiation ogntllrnelatresia. laryngeal congenital coupling. excitation-transcription 707-711. , 10 20) utie ciaino TT sesnilfrcrmtnremodeling chromatin for essential is STAT5 of activation Sustained (2009). 75-82. , n.J ice.Cl Biol. Cell Biochem. J. Int. 4 247-256. , 535 16) oiinlifrainadtesailpteno cellular of pattern spatial the and information Positional (1969). 20) eesn lo lw c hog l2 oesr normal ensure to klf2a through act flows blood Reversing (2009). 87-93. , .Ter Biol. Theor. J. ehnsniietasrpin3073 transcription Mechanosensitive .Cl Sci. Cell J. adoac Pathol. Cardiovasc. eit.Pathol. Pediatr. 20) tanidcdftltp Ieihla cell epithelial II type fetal Strain-induced (2006). .Ci.Invest. Clin. J. a.Rv o.Cl Biol. Cell Mol. Rev. Nat. 25 20) h oeo h coysnctseeo in cytoskeleton actomyosin the of role The (2007). 18) nrtoai rsue nftlsheep. fetal in pressures Intrathoracic (1982). 20) yi n ailnpoen:fcladhesion focal proteins: paxillin and Zyxin (2003). 120 1-47. , .Cl Biol. Cell J. 21) rncitoa euaino er valve heart of regulation Transcriptional (2011). 291 Gene 20) ehntasuto ndvlpet a development: in Mechanotransduction (2009). 1801-1809. , 40 1659-1663. , L820-L827. , Science LSBiol. PLoS 19) ehntasuto costecell the across Mechanotransduction (1993). 363 20) ehntasuto tadistance: a at Mechanotransduction (2009). si . au,A n culc,C A. C. McCulloch, and A. Kapus, K., ´szi, ici.Bohs Acta Biophys. Biochim. 21) h ip-A aha norgan in pathway Hippo-YAP The (2010). 20) eeiiemcaia stretching mechanical Repetitive (2005). 166-172. , 106 itoa ciaino h vascular the of activation riptional 7 260 183 515-525. , 20 20) ehnsnoycomplex mechanosensory A (2005). 1321-1330. , .Cl Biol. Cell J. 162-167. , 1124-1127. , 849-863. , 7 ee Dev. Genes e1000246. , 18) ea uggot in growth lung Fetal (1987). .Ci.Invest. Clin. J. 19) novmn fprotein of Involvement (1994). 20) ux:o oeand bone of Runx2: (2008). 10 20) aioahe and Laminopathies (2009). ur Biol. Curr. 34-43. , 20) Stretch-induced (2000). 184 Nature 24 a.Rv o.Cell Mol. Rev. Nat. 1593 57-66. , 862-874. , 119 Carcinogenesis 17 115-120. , 437 1349-1355. , 1825-1836. , 426-431. , (2008). .Dev. J. m J. Am.