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Mechanotransduction
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Mechanotransduction
PAULA.SUNDARAM
UniversityofPuertoRico,Mayagüez,PuertoRico
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Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythe Publisher(otherthanasmaybenotedherein).
Notices
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Dedication
Mywife,Fabiola,whoismyperfectcomplement, mytruecompanion,withoutwhomIwouldbeincomplete.
Mychildren,PaolaAlejandraandJulianPatrick,whoaremycrown andjoyandhopefullywillcarrythetorchforward.
Myparents,ChandranandVimala,whotaughtmetheimportant thingsinlife.
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Preface xi Acknowledgments xiii
Foreword xv 1.Introduction1
2.Cellsignaling:Anoverview7
2.1 Introduction 7
2.2 Modesofcellcommunication7
2.3 Phasesincellsignaling9
2.3.1 Reception9
2.3.2 Transduction13
2.4 Response 18
2.5 Mechanicalsignalingincells20
2.5.1 Cellstructuralelementsthatareimportantinmechanicalsignaling20
2.5.2 Mechanosensingormechanoreception24
2.5.3 Signaltransmission24
2.5.4 Targetactivation25
2.5.5 Geneexpression25
3.Cellsignalingundermechanicalstimulusinspecificcelltypes29
3.1 Introduction 29
3.2 Forcesactingoncells29
3.3 Modesofmechanosensing30
3.4 Factorsaffectinggeneralcellresponse33
3.4.1 Stressstateofthecell33
3.4.2 Substratecharacteristics34
3.4.3 Temporalresponseofcellstoappliedmechanicalstimulus35
3.5 Cellmechanotransductioninmusculoskeletaltissue37
3.5.1 Typesofcellsinbonetissue37
3.5.2 Themechanosensoryenvironmentofbonecells38
3.5.3 Themechanoreceptorsinbonecells39
3.5.4 Signalingpathwaysinbonecells40
3.5.5 Theresponseofbonecellstoappliedmechanicalstimulus43
3.6 Cellmechanotransductionincartilage43
3.6.1 Mechanicalenvironmentofcartilaginouscells43
3.6.2 Mechanismsofmechanotransductioninchondrocytes43
3.7 Cellularmechanotransductioninpulmonarytissue44
3.7.1 Typesofcellsinlungtissue44
3.7.2 Mechanicalenvironmentinthelung45
3.7.3 Mechanismsofmechanotransductioninthelung46
3.8 Cellmechanotransductionisthecardiovascularsystem48
3.8.1 Typesofcellsinthecardiovascularsystem48
3.8.2 Mechanicalenvironmentforcardiovascularcells48
3.8.3 Mechanismsofmechanotransductionincardiovascularcells49
3.9 Cellmechanotransductioninnervetissue52
3.9.1 Typesofcellsinthenervoussystem52
3.9.2 Mechanicalenvironmentfornervecells53
3.9.3 Mechanismsofmechanotransductioninthenervecells54
4.Cellcharacteristicsresultingfrommechanicalstimulus57
4.1 Introduction 57
4.2 Effectofmechanicalstimulionnormalcells57
4.2.1 Typesofmechanicalstimuli57
4.2.2 Influenceofmechanicalfactors58
4.2.3 Effectofsubstratecharacteristics59
4.2.4 Effectofscaffoldproperties60
4.2.5 Mechanotransductionatthemolecularlevel61
4.3 Effectofmechanicalstimulionstemcells67
4.3.1 Incongruencyincellresponse67
4.3.2 Typesofmechanicalstimuli68
4.3.3 Stemcellresponsetomechanicalstimuli69
4.4 Effectofmechanicalstimulioncancercells74
4.5 Theroleofcelladhesionmoleculesinmechanosensing80
4.6 Cellularproliferation82
4.7 Extracellularmatrixremodeling84
5.Tissuemechanotransduction91
5.1 Introduction 91
5.2 Signalcharacteristics93
5.3 Signalcontrol:Structuralandsecretoryfactors95
5.3.1 Adherensjunctions95
5.3.2 Gapjunctions95
5.3.3 Secretoryfactors96
5.4 Musculoskeletalsystem97
5.4.1 Mechanophysiologicalenvironment97
5.4.2 Mechanotransductioninmusculoskeletaltissue102
5.5 Pulmonarysystem104
5.5.1 Mechanophysiologicalenvironment104
5.5.2 Mechanotransductioninpulmonarytissue107
5.6 Cardiovascularsystem108
5.6.1 Mechanophysiologicalenvironment108
5.6.2 Mechanotransductionincardiovasculartissue111
5.7 Nervoussystem112
5.7.1 Mechanophysiologicalenvironment112
5.7.2 Mechanotransductioninnervetissue113
6.Mechanotherapy117
6.1 Introduction117
6.2 Mechanotransductionanddisease118
6.3 Mechanotherapy:Molecularscale124
6.4 Mechanotherapy:Tissuelevel125
6.5 Emergingtrendsinmechanotherapy126
6.6 Cancertherapyandmechanotransduction127
6.7 Othertherapeuticeffectsofmechanicalstimulus127
7.Futurethrustsinthefieldofmechanotransduction129
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Preface
Mechanotransductionisacomplextopicwhichinvolvesalotofbiologybutalso mechanicalforcesanddeformations.Aconcisetextbookdedicatedtothistopicis unavailablewhichcouldbringtogethercomplextopicssuchascellsignalingandcell responsefortheengineeringstudentandassembleitwiththeconceptsofmechanical stressandstrainwhichwouldbedifficulttograspforstudentsinbiology.Ofcourse, thefieldofmechanotransductionisrifewithresearcharticleswhicharechallengingfor earlygraduatestudentsinengineeringwhohavelittleornobackgroundinbiology.It dawnedonmethatatextbookonmechanotransductionifwritteninasimplemanner wouldbeavaluabletoolforstudentsinbothengineeringandbiology.Thisbookwill beastartingpointforstudentstograspthebasicconceptsofmechanotransductionand focusonspecificreviewarticlestogetamorein-depthknowledge.
ThebookiswrittenissuchafashionsoastointroducetheconceptofmechanotransductioninChapter1,Introductionaswellassomeofitspracticalimplicationsin thehumanbody.Thisisfollowedbythefundamentalprinciplesofsignaltransduction incellsincludingsignalreception,transduction,andresponseinChapter2,Cellsignaling:anoverview.Chapter3,Cellsignalingundermechanicalstimulusinspecific celltypesdelvesintotheeffectofmechanicalstimulusonvariouscelltypes.Attention ispaidtosomespecificcelltypeswhichhavebeenstudiedinsomedetailinliterature. Chapter4,Cellcharacteristicsresultingfrommechanicalstimulusdealswithchanges incellcharacteristicsundertheinfluenceofmechanicalstimulusincludingtheeffect onstemcells,cancercells,cellproliferation,andremodelingoftheextracellular matrix.MechanotransductionintissuesisdescribedinChapter5,Tissuemechanotransductionwiththegoalofunderstandingtheinfluenceofmechanicalstimulusin largergroupsofcellsortissues.Thepracticalapplicationsofmechanotransductionin actualclinicaltreatmentsthroughmechanotherapyarepresentedintheChapter6.
Chapter7,Futurethrustsinthefieldofmechanotransductionsuggestssome topicswhichareworthresearchinginfurtherunderstandingthebroadthemeof mechanotransduction.
Eachchapteriswritteninaformthatitcanbetreatedindependentlybutthereisa connectionbetweenthechaptersalso.Attheendofmostofthechapterstherearea fewquestionsunder “reviewandproject” toenablethestudenttoresearchandthink furtheraboutsomeofthesetopics.Itismyhopethatthisbookbringstheconceptsof mechanotransductioninaclearandsimplemannertothestudenttobuildafirm foundationuponwhichmorecomplexconceptscanbeconstructed.
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Acknowledgments
Thedesiretowriteatextbookthatwouldbeaccessibletostudentsmotivatedmeafter Ifirsttaughtagraduatecourseincellmechanicsin2012.Toteachthecourse,Ihad tousematerialfromavarietyofsourcesincludingbooks,researcharticles,and reviews.Idecidedtowriteabookonmechanotransductionsinceatextbookonthis topiciscurrentlyunavailable.Writingthisbookwasamajorprojectandmanypersons weredirectlyorindirectlyinvolvedfromconceptualizingittoitsbirthing.When Elsevierapproachedmewiththeideaofwritingabook,Itookthebait,neverfora momentimaginingthemanychallengesthatthisprojectwouldbringalong.Iwas convincedtocomeupwithatitleandatableofcontents.WhenIfirstproducedthe tableofcontents,thebookbegantotakeshape.TheElsevierPublishingteamquickly tiedmeintoacontractfromwhichtherewasnoturningback.Duringthecourseof writingthesamplechapter,thepublishingeditorFionaGeraghtypassedthebatonon toFernandaOliveirawhohasbeeninstrumentalingettingthisbookout.The Elsevierteamworkedwithme,handinhand,toensuretimelydelivery.Thebookin finallyarealityforwhichIamgratefultoElsevier.
Ofcourse,theimpetustowriteonthistopicdefinitelycamefrommygraduate studentsattheUniversityofPuertoRico,Mayaguez.Eachoneofthem,throughtheir painstaking,forward-thinkingresearchhavesomehowmademethinkmoreprofoundlyaboutthephenomenonofmechanotransductionandhowtosuccinctlyrelay complexconceptstostudentswithclarityandsimplicity.Itwouldnotbesuperfluous toemphasizethatmystudentswerethedriversforthisoutput.Iam,ofcourse,gratefultotheDepartmentofMechanicalEngineeringattheUniversityofPuertoRicoat Mayaguezforalwaysprovidingmethespaceandsupportthroughoutmycareer.
Finally,thewritingofthisbookbecameafamilyproject.Iamgratefultomywife andchildrenfortheirpatiencewhenIwasabsorbedandsometimesobsessedwith writingtoproduceatextbookpalatableforthestudent.Mywifeanddaughtercreated,designed,andproducedmanyoftheillustrationsinthemanuscript,without whichthisbookwouldnothavebeenfinished.IcannotbutbegratefultotheKing ofkingsandLordoflordstowhomallgloryisdue.
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Foreword
Haveyoueverstoppedtoponderhowthebodyworks?Morespecifically,how,asa complexmachine,doesthebodydevelopandsustainintegratedformandfunctionof allitsworkingtissueandorgancomponents?Toaddresssuchquestions,onemust embracemechanobiology,afieldthatoperatesattheinterfaceofbiology,engineering, andphysicstodescribehowphysicalforcesatthemolecular,cellular,andtissuelevels guidetissuedevelopment,physiology,anddisease.Fundamentaltomechanobiologyis mechanotransduction,theprocessbywhichcellssenseandrespondtophysicalstimuli byconvertingthemtodownstreambiochemicalsignals.PaulA.Sundaram’sbook, Mechanotransduction:CellSignalingtoCellResponse,bringstogetherthelatestdevelopmentsinthefieldofmechanobiology,providingarichfoundationonthefundamental cellmachineryandassociatedmechanotransductionprocessesinvolvedinhealthand disease.Thisincludesdefinitionoftheunderlyingmechanismsbywhichvariouscell typesmodulatetheircharacteristicsandbehaviorsinresponseto(1)physicalforces (e.g.,fluidshear,tension),(2)stiffnessofthesurroundingextracellularscaffold,and (3)connectivitywithothercells,withreferencedapplicationsspecifictotissueand organsystems,includingmusculoskeletal,cardiovascular,pulmonary,andnervous. Thelatterchapters,focusonhowfundamentalmechanobiologyandmechanotransductionprinciplesareinspiringdesignanddevelopmentofengineeredtherapeutics, devices,andcomputationalsimulations,withapplicationsinmedicine.Thisbook isdesignedforreadersfromallrelevantfields,includingengineering,lifesciences, physicalsciences,andcomputationalsciences.Itprovidesanexcellentreferenceand currentupdateforthosenewtoorcurrentlyworkingwithinthemechanobiology arena.Thisbookrepresentsatimelyproductionandishighlyrecommendedtoall.
SherryL.Harbin
WeldonSchoolofBiomedicalEngineeringand DepartmentofBasicMedicalSciences,PurdueUniversity, WestLafayette,IN,UnitedStates
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CHAPTER1 Introduction
Thetrillionorsocellsinthehumanbodyaredividedintofunctionalgroups,whichactsynchronouslyandinahighlycoordinatedmannerinperformingthebody’sphysiologicalfunctions.Allthesecellsarecontrolledbymeansofsignals,whicharestimuliofvarioustypes, whichprovidethespecificimpetusnecessarytoelicitthecorrespondingfunction.Manyof thesestimulatorsarechemicalinnaturealthoughthewideimpactandtheroleofphysical parameters,includingmechanicalforcesandfactorsinrealizingroutinefunctions,cannotbe denied.Inbiologicalterms,simplyput,inall ifnotmostprocesses,thereisareceptionof thesignal,anappropriatetransduction,whichismanytimesunknown,andaresulting action,whichbringsaboutaresponsefromthetargetwhetheritisanorganoratissueora cell.Forexample,clearly,thereissomechemicalsignalingoccurringthroughneurotransmission,whichcausesbothvoluntaryandinvoluntarymusclemovement.Theobviousphysical movementofourlimbsandotherpartsofthebodyisaccomplishedbyacomplexsetofsignalsandtransduction.However,whenwelook atmoresubtlemechanicalstimuliasinitiatorsofnormalphysiologicalfunction,thereisnodenyingtheaddedinvolvementofthe mechanicalforcesexertedbythecardiacpumpincirculatingthelargevolumeofblood throughoutthebody.Theflowofbloodexertsamechanicalforceonthebloodvessels whosecellsareconstantlysubjectedtoastretchingandrelaxingforcevariations.Peristalsisis theundulatingmovementofthemusclesandinvolvesthetransportoffoodfromthemouth tothestomachthroughmechanicalforces.Theabsorptionofnutrientsattheintestinesalong thistrajectoryandfinallyexcretionaccomplishedthroughbowelmovementisalsovery muchamechanicalaspectofourbodilyfunctions.Normalbreathingisyetanotherexample whereacyclicforceisimposedoncellsthatlinethelungtissuewithprecisionandconsistency.Mechanicalforcesbecomeespecially importantinembryonicdevelopmentduring thegastrulationphase.Thesensitivityofmost,ifnotall,cellsinthehumanbodytophysical ormechanicalforcesisundeniable.Wewilllookatmorespecificexamplesaboutindividual cellsandcellgroupsortissuesandunderstandtheparticularroleplayofmechanicalstimuli andthecorrespondingtransductiontoaccomplishphysiologicalfunctionsingreaterdetailin thechaptersthatfollow.
Whilegrossphysiologicalfunctionssuchaskinesisorcardiacfunctionareobvious factsinrelatingandappreciatingtheimportanceofmechanicalforcesinthehuman body,therearemanymoresubtleeffectsthatescapeourattention.Proteinexpression andconformationareverymuchcontrolledbymechanicalfactorsatthecellularlevel. Infact,theabsenceordeficiencyofphysicalparametersincellularfunctionshas
resultedinanumberofpathologicalconditions,disease,anddysfunction.Theroleof mechanicalforcesinorganogenesisisincreasinglyevident,andscientistshaveslowly realizedtheutmostsignificanceofthemechanicalinteractionbetweenacellandits microenvironment,includingneighboringcellsaswellastheextracellularmatrix.
Whiletheinterestintheeffectofmechanicalfactorsoncells,tissues,andorgansis undeniable,onlyinrecentyearshastherebeenanuptrendintheinterestinunderstandingthesephenomena.Theeffectsofmechanicalstimulihavebeenreportedin theliteratureforquiteawhile,buttheircriticalrolesintheproliferationofcells,cell differentiation,motility,proteinsynthesis,etc.areonlybeingrecentlyresearched.The mechanismsunderlyingthepositiveandadverseeffectsoncellsarebeinglookedat fromthefundamentalperspective;ideasontheseareproposedbasedonexperimental evidenceandreported.FromtheearlypublicationofD’ArcyThompson,scientists havereportedvariouseffortstounderstandtheeffectsofthemechanicalmanipulation ofcells.However,afirmreferenceregardingtheinfluenceofmechanicalforcesatthe cellularlevelgainedstrengthonlyinthe50s.Sincethen,ourunderstandingofthe interplaybetweenbiologicaleventsinfluencedbymechanicalforceshassteadily increasedwithcriticaldiscoveriesresultingfromthedevelopmentofinnovative experimentaltechniques.Thisconceptofmechanochemicaltransduction(mechanical stimuliproducingbiochemicalresponses)anditsroleinanumberofphysiologicaland pathologicalconditionsgavefurtherimpetustothestudyofthisphenomenon.
Fromtheearlydiscoverythatcancercellscouldbecomeadherentandspreadonsoft agartothemechanosensingcapabilityoftheplasmamembrane,ithasbecomeevident thatphysicalforcesplayanimportantroleincellphysiology.Thetensiondifferential betweentheinnerandoutercellmembranelayersinerythrocytes,whichleadsto changesincellshape,wasanimportantstepinunderstandingcellmigration.Armed withtheexperimentaldataandtechniquestoreportevidenceofionchannelactivation byshearstressandthediscoveryoftheintegrinfamilyofproteins,the1980sopenedthe fieldofmechanotransductiontoanewlevel.Withthedevelopmentofsophisticated experimentaltechniques,theunderstandingofthemechanismssuchasintegrinmediatedmechanotransductionbecamemoreaccessible.Theinnovativetechniqueof TractionForceMicroscopyenabledthemeasurementofsmall-scaleforcesthatcells applyontheirsubstrates,andtheuseofAtomicForceMicroscopy(AFM)toresearch theunfoldingofproteinsfollowedbytheabilityovertheyearstodelveevendeeper intominisculestructuressuchastheresponseoftalintomechanicalstimulihasgivenus amoreprofoundunderstandingoftheeffectofmechanicalstimulionbiological responsesincells.AFMwasskillfullyutilizedtostretchproteinsanduncoverdomains thatheretoforeunknown.Morerecenttechniquesthathaveenabledtheresearcherto obtainnanoscaleresolutiontotrackthestretch relaxationcyclesofproteins.Novel fluorescencetechniquesexposedthepresenceofmoleculessuchaspaxillin,talin,focal adhesionkinase,etc.inthefocaladhesioncomplexes.Withsuchadvances,itis
completelyfeasibletoquantifycell-scaleforcestoahighlevelofprecisionandstudythis parameteratdifferentscales.Inthelatterhalfofthefirstdecadeofthe21stcentury,the firstfluorescenceresonanceenergytransfer-basedproteinstretchsensorwasdeveloped. Invivotechniquesgainedpopularity,aslive-cellimagingoftalin,vinculin,andother connectorshelpedourunderstandingofmechanosensors.Somewhereinthishistorical timeframe,theterm mechanotransduction wasintroducedtodescribethecellphysiology processwherebycellsconvertmechanicalstimuliintobiologicalresponses.Innovative experimentationandnewlydevelopedtechniqueshavegreatlyhelpedustounderstand theessenceofmechanicalstimulioncells,tissues,andorgansinthathierarchicalorder. Thus,ithasbecomepossibletounderstandtheeffectofmechanicalforcesandthecorrespondingcellresponseinanevenmoreprofoundmanner. Fig.1.1 isahistoricaltimelineofthedevelopmentofthestudyof mechanotransduction andthesignificantmilestones reachedinthisprocess.Therecentdevelopmentofsophisticatedinstrumentationhas enableddiscoveryandobservation,identification,anddescriptionofseveralintracellular molecularmechanisms.Substrateswithsubmicronpost-likestructureswerefabricatedto allowforthemeasurementofcellstress.Morerecently,celldivisionhasbeenhypothesizedtobecontrolledbymolecularmotors,whichoperateinconjunctionwiththe microtubule-organizingcenterstobringaboutthisfunction.Also,areportaboutconstantcommunicationbetweentheendoplasmicreticulumandmitochondriathrough localtransportwasrecentlyhighlighted.
Figure1.1 Atimelineofimportantmilestonesincludingdiscoveriesanddevelopmentofinstrumentation,whichhasledtothephenomenalgrowthofthefieldofmechanotransductioninthe lastfewdecades. AFM,AtomicForceMicroscopy; FRET,FörsterResonanceEnergyTransferor FluorescenceResonanceEnergyTransfer; TFM TractionForceMicroscopy; RPTP;ReceptorProtein TyrosinePhosphatase. DatatakenfromIskratschT,WolfensonH,SheetzMP.Appreciatingforceand shape-theriseofmechanotransductionincellbiology.NatRevMolCellBiol2014;15(12):825 33.
Thetermmechanotransductionhasnowbeengenerallyacceptedtodefinethe conversionofmechanicalsignalsintobiochemicalorbiomechanicalresponsesinthe cellandfurtherextendedtoincludetissuesandorgans.Asinothercellsignaling mechanisms,mechanotransductioninvolvesasensoryorreceptionphase,atransductionphase,andaresultingactioninandbythecell.Stretch-sensitiveionchannelsand theinteractioninvolvingtheextracellularmatrixandthecytoskeletonhavenowbeen acceptedasstandardmechanosensorsorreceptorsandanumberofintracellularsignalingpathwayshavebeenidentified,whichregulategeneexpressionandprotein synthesis.These,inturn,arecriticaltocellmetabolismorphysiologicalfunction.The importanceofthesefunctionsinsystemoperationinvolvingorganfunctioncannotbe overemphasized.
Thereisnodenyingthefactthatthewidegamutofeventsfurtherexacerbatesthe difficultyinpinpointingjustoneortwomechanotransductionprocessesascontrolling alltheseoccurrences.Rather,acombinationofsuchmechanotransducersmustbe accountedfortoaccomplishsuchacomplexarrayofphysiologicalevents.Acertain specificmechanicalstimuluscanprovoketheoperationofvarioussignalingmechanismsandaccomplishavarietyofcorrespondingphysiologicalfunctions.Ontheother hand,varioustypesofmechanicalstimulicanresultinthesamecellresponse.
Preciseactionsatthemicroscalearenormallyrequiredtocauselarge-scalechanges atthetissue,organ,oreventhesystemlevel. Table1.1 showsestimatedvaluesof mechanicalstimulionvariouscellsandhighlightstherathersmallvaluesnecessaryto drivelarge-scalechangesinthecorrespondingtissueororgan.Inthemajorityofphysiologicalchanges,proteinexpressionisultimatelyresponsible,andmanysignalingcascadesatthecellularleveldependonconformalchangesintheproteinstructure.
Table1.1 Estimatedmagnitudesofmechanicalstimulioncellinvivo.
PhysicalprofileMechanicalstimulusMagnitudes
ArterialbloodflowFluidshearstress1 3Pa
CellmigrationTractionstress3 5.5kPa(normalcells)
1kPa(cancercells)
ProximaltubuleflowFluidshearstress0.3Pa
Fluiddragforce0.0074pN/microvillus
Bendingtorque0.016pN-mm/microvillus
Stretch-activatedchannelsMembranetension0.012N/m
OuterhaircellstereociliaCompressionstiffness0.01N/m Force/Dmembranepotential0.020.1 20pN/mV
BonecanaliculiFluidshearstress0.8 3Pa
Fluiddragforce20 3 shearforce Tissuestrain0.03% 0.1%
Source: AdaptedfromOrrAW,HelmkeBP,BlackmanBR,SchwartzMA.Mechanismsofmechanotransduction. DevelopCell2006;10(1):11 20.
Fromathermodynamicperspective,theseconformalalterationsmustbeaccompaniedbyadecreaseinfreeenergyofthereactionorprocess.Inextendingthisargumenttoprocessesinvolvingmechanicalstimuli,thechangesinproteinconformation mustsupporttheconsequentdecreaseinfreeenergy,failingwhichaprocesswillnot occur.Forexample,anincreaseintensionwithinthephospholipidbilayerwillresult intheactivationoropeningofstretch-activatedionchannelslocatedincellmembrane providedthatthechangeinsurfaceareawillresultinadecreaseinfreeenergy.
Thustheimportantroleofmechanotransductioninthesedevelopmentalprocesses cannotbeunderstated,andthedrasticchangesincellmovement,whichoccurduring embryogenesisduringgastrulationandneurulation,mustbeaccompaniedbyafree energydecrease.Itappearsthatafeedbackloopfromtheforcesexertedonthetissues duringembryogenesisguidestissuemovement.Itisspeculatedthatmechanotransductionresultingfromfluidflowcontrolstheformationofleft rightasymmetryduring embryonicdevelopment.Also,themorphologyofthecardiovascularsystemishighly influencedbythemechanicalstimuliexertedbythebloodflowviapressureon smoothmusclecellsinthelumenandshearstressontheendotheliallining.Bonetissueisshapedbytheforcesappliedonitbymuscles.
Inthefollowingchapters,asequentialbutexclusivedevelopmentofthegeneral topicofmechanotransductionisprovidedwiththeadditionaldetailnecessarytodelve deeperintothesubject.Asacaveat,mechanotransduction,inonesense,isstillafledglingthemewithimportantimplicationsinhumanhealth. Chapter2,CellSignaling: AnOverview,providesafairlydetaileddescriptionofcellsignalingincludingthetrifectaofreception,transduction,andproteinsynthesis. Chapter3,CellSignaling UnderMechanicalStimulusinSpecificCellTypes,dealswithcellsignalinginspecific celltypesinresponsetomechanicalstimulus,followedbychangesinthecharacteristics ofnormalandcancerouscellsandthebehaviorofstemcellsin Chapter4,Cell CharacteristicsResultingFromMechanicalStimulus.Mechanotransductionatthetissuelevelanditseffectonorganfunctionwillbedealtwithin Chapter5,Tissue Mechanotransduction.Theroleofmechanicalforcesindiseaseevolutionaswellas conceptsinmechanotherapytoexploitthepositiveeffectsofmechanicalloadsand strainsonhumanhealthwillbehighlightedin Chapter6,Mechanotherapy.Thelast chapterwillshedsomelightonfutureopportunitiestofurtherstudythisemerging andexcitingfieldofmechanotransduction.
ReviewandProject
1. Writealistof4-5situationswheremechanicalstimulusisappliedinthehuman bodytobringaboutphysiologicalfunction.
2. For2or3oftheabovecases,indicatethestimulus,thepossiblesignaltransduction ingeneraltermsandtheresponse.
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CHAPTER2
Cellsignaling:Anoverview
2.1Introduction
Thepurposeofasignalinacellistoaccomplishsometypeofphysiologicalfunction. Hence,thecellhastoreceiveasignal,whichthenresultsintransductionwithinthecelland ultimatelycausesthecelltoperformitsfunction.Inanutshell,theoverallmechanismincell communication,includingtheinitiationandresponsetoasignal,consistsofthreedistinct phasesorsteps:(1)signalreception,(2)signaltransduction,and(3)signalresponse.Thecell receivesasignalthroughligandbindingwitha receptorprotein,whichhasbothanextracellularportiontocapturethesignalandanintracellularorcytosolpart,whichtransmitsthesignaltootherintracellularproteinsinaprocesscalledtransduction.Thesignalisfinallyreceived byeffectorproteins,whichaccomplishthephysiologicalfunctionofthecellastheresponse. Inwhatfollows,abird’s-eyeviewofthecellsignalingprocessisprovidedwithoutattempting togetintodetailsofadvancedbiochemicalreactionsthatoccurintheseprocesses,whichare beyondthescopeofthisbook.However,sufficientinformationisprovidedforthereaderto graspthefundamentalsofcellsignaling.Advancedstudentsaredirectedtostudythisphenomenoninmanyresearcharticlesthatareavailable,whichdealspecificallywiththistopic.
2.2Modesofcellcommunication
Cellsignalingentailsthetransmissionofinformationfromonecelltoanothercellora groupofcells.Hence,cellsmustbeabletocommunicatewitheachothertopass alongthisinformationonward.Faultycommunicationbetweencellsresultsindeficiencyinthetransmissionofinformation,which,inthehumanbody,mayleadto pathologiesordisease.Inacomplexmulticellularsystemsuchasthehumanbody,itis imperativethatthereiseffectivecommunicationbetweendifferentcellgroupsfor properfunctioningofthesystem.Itshouldbenotedthatthereisaredundancyinthe signaling,resultinginthesamecellfunction,incasetheprimarysignalisunableto accomplishitsobjectivebecauseofadeficiencyinthatsignalingpathway.Thereisa plethoraofcommunicationpathwaysbetweencellsandgroupsofcells.Cellsrespond toavarietyofsignals,whichcanbeclassifiedaschemicalandmechanicalstimuli.Ina generalsense,allcellsaresubjectedtosomekindofsignaling,whichelicitsaphysiologicalresponse.Ifwethinkaboutasimplesensationsuchashunger,theinitialsignal comesfromthepituitarygland,whichinandofitselfistriggeredbyalackofenergy productioninthebody.Thissignalisfollowedbythesecretionofgastricjuicesinthe
stomach,whichcausesa “burning” sensation,creatinganurgeinustoconsumefood. Thefeedbackfromtheenergygeneratedbythebreakdownofsugarsfromthefood thatwasingestedresultsinthesignalbeingshutoffuntilmoreenergyisneeded.
Whenananimal,letussay,forexample,alioness,huntsforherprey,thesensationof hungerdriveshertoidentifytheprey,stalkthevictim,hunt,andkillit.Althoughthis appearstobeasimpleprocess,onecanimagineatthecellularlevel,themanytypesofcells thatareactivatedbyaninitiator.Inthiscase,thehormoneepinephrineisthetrigger,which providesincreasedenergyforthelionesstochaseherprey,overpowerit,andthendeprive itoflife.Duringthisprocess,acomplexinteractionandactivationofdifferentcellgroups withspecificfunctionsprovidesaheightenedsenseofhearing,sight,abilitytoaccelerateto highspeeds,andbrutestrengthtokillthepreyjustthroughthereleaseofepinephrinefrom theadrenalglands.Thesameadrenalinerushistheeffectorforthepreytorunfasterandbe awareofitshunter,withthegoalofescaping thelionessandpreservingitslife.Inhuman beings,thesamesensationisexperiencedwhenwefeelweareindanger,asepinephrineis releasedintoourbloodstream.Comparethesesurvivalinstinctsinspecialcircumstanceswith thenormalactivityofapersonwhohastoartificiallycreatethisheightenedstateduring strenuousphysicalexercise.Inthiscase,thereleaseofepinephrineiscoercedbytheintense levelofphysicalactivityimposedonthehumanbody.Itisnotsurprisingthenthatto accomplishthesehighlycomplextasks,communicationbetweengroupsofcellsbecomes criticaltothehealthyphysiologicalfunctioningofthehumanbody.
Cell-to-cellcommunicationisaccomplishedinavarietyofwaysdependingonthe proximityofthesignalingcelltothetarget cell,aswellasthefunctionthatthesystem aimstoaccomplish.Thesimplestcommunicationpathisthroughautocrinesignaling wherethecellinitiatingthesignalandtherespondingcellareoneandthesame.Another methodofcommunicationbetweencellsisthroughthedirectcontactoftheinitiatingcell withanothertargetcell.Thesignalinitiatingcellcomesintocontactwiththetargetcell andsecretesthechemicalagent(signal)thatisnecessarytoaccomplishtherequiredfunction.Thissignaltransmissionisenabledby meansofintercellularconnectionscalledgap junctionsthroughtheexchangeorpassageofsmallmolecules.Gapjunctionsaretransmembranalstructuresthatconnectadjacent cellsandenablethetransportofsmallmoleculesandions(particularlyCa21 )betweenneighboringcells.TheinductionofBcells, whichcomeindirectcontactwithhelperTcellsatthethreatofantigensinourimmune system,isanexampleofcellcommunication bydirectcontact.Thesecretionofneurotransmittersinthesynapticjunctionsisan exampleofanothertypeofcellcommunication calledparacrinesignalingwherethesignalingcellandthetargetcellareincloseproximity toeachotherbutnotindirectcontact. Fig.2.1 isasimpleillustrationofthereleaseof neurotransmittersinthesynapticjunctionfromthepresynapticaxonandfurthertransmissionofthiscommunicationdownthelinetotheproximalpostsynapticaxon.Suchtype ofsignalisanexampleofcellcommunication,inthiscase,specifically,paracrinesignaling, generatedfrequentlyinthe gastrointestinaltract.
Figure2.1 Typicalcellcommunication.Simpleillustrationoftypicalcell cellcommunication.In theexampleshown,thereleaseofneurotransmittersfromoneaxonintothesynapticjunctionof theneighboringaxonresultsinthetransmissionofacellsignal.
Theproductionofhormonesbythepituitaryglandtoaccomplishaphysiologicalfunctionfarawayfromthepointofreleaseisathirdcellcommunicationmethodknownas endocrinesignaling.Inthiscase,thehormone,whichisthesignalingmolecule,isreleased intothebloodstreamandtravelsarelativelylongdistancetotriggeranappropriateresponse inanothercellgroupmuchfartheraway.Thedistanceeffectoncellsignalingissummarizedin Fig.2.2.
2.3Phasesincellsignaling
Thecellsignalingprocesscanbedividedintothreedistinctphases,whichoccurinthefollowingorder,reception,transduction,andresponse. Thismeansthattransductioncannottakeplace beforereceptionandneithercanresponseoccurbeforesignalreceptionandtransduction.
2.3.1Reception
Cellsignalingisnormallyinitiatedwhenasmallmoleculeorevenalargerproteinis releasedbyonesetofcellstotriggeraresponse.Thisinitiatorsignal,commonlycalled aligand,attachestoacellreceptor,asseenin Fig.2.3.Thissignalingmoleculeis
