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    首頁 4.StemCells醫學電子書

    4.StemCells醫學電子書.pdf

    4.StemCells醫學電子書

    小嘎
    2018-04-02 0人閱讀 舉報 0 0 暫無簡介

    簡介:本文檔為《4.StemCells醫學電子書pdf》,可適用于醫藥衛生領域

    InterventionsinAgingandNeurodegenerativeDisease:EffectsonAdultStemCellsAdamDBachstetter,CarmellinaGemma,andPaulaCBickfordAbstractThroughouttheentirelifespan,stemcellsarepresentinmanyorgansofourbodyandcontinuetoproducenewcellswhicharecriticaltomaintainhomeostasisandtorepairdamagedtissuesInthebrain,stemcellsgeneratenewneuronsthroughaprocesscalledneurogenesisWithage,stemcellslosetheirabilitytogeneratenewcells,althoughthenumberofstemcellsremainsconstantovertimeThismaybedueinparttocellularstressessuchasinflammation,oxidativestress,andlossoftrophicfactorsthataccumulatewithageAbetterunderstandingoftheregulatoryfactorswhichcontrolneurogenesisisnecessaryinordertoutilizethepotentialoftheendogenousadultstemcellstotreatthedegenerativeconditionAbbreviationsAD:AlzheimerrsquosdiseaseCNS:centralnervoussystemGCL:granulecelllayerIL:interleukinNSAID:nonsteroidalantiinflammatorydrugNSCs:neuralstemprogenitorcellsOHDA,hydroxydopaminePD,ParkinsonrsquosdiseaseSGZ:subgranularzoneTNF:tumornecrosisfactoraIntroductionNeurodegenerativediseasesofagingsuchasAlzheimerrsquosdisease(AD)andParkinsonrsquosdisease(PD)areassociatedwithaprofoundlossofsynapticplasticityandregionallyselectivecelllossAsimilarlossofsynapticplasticityalsooccurswithnormalaging,albeitnotassevereandwithlessevidenceforcelllossThecausesofthelossofsynapticplasticityaredebatablebuttheresultsarecleartothepatientswhosufferfromthisdevastatingdiseaseAsthepopulationages,thereisapressingneedtodeveloptherapeuticinterventionsforagerelatedneurodegenerativeRBMaccioniandGPerry(eds)CurrentHypothesesandResearchMilestonesinAlzheimerrsquosDiseaseDOI:,copySpringerScienceBusinessMedia,LLCADBachstetter,CGemma,andPCBickford()CenterofExcellenceforAgingandBrainRepair,CollegeofMedicine,UniversityofSouthFlorida,Tampa,FLemail:pbickforhealthusfeduADBachstetteretaldiseases,bothforthepatientandforthosewhowillhavethedemandingresponsibilitytocareforthemOneaspectofneuralplasticityisneurogenesisItisnowwellacceptedthatneurogenesisoccursinatleasttwogerminalcentersinthebrainOneoftheneurogenicregionsisthesubventricularzoneTheotherknownregionfoundinthehippocampusisinthesubgranularzone(SGZ)ofthedentategyrus,whereneurogenesishasbeenfoundinhumansasoldasyearsofageAdditionofnewneuronstothebrainiscomplementarytosynaptogenesis,whichisanothermeansofsynapticplasticityUnderstandingthemechanismsthatregulateneurogenesisisnecessarytoutilizethispotentialreservoirofsynapticplasticitytoincreasethequalityoflifeofouragingpopulation,withandwithoutADTherearefivephasesofhippocampalneurogenesis:Thefirstphaseisproliferationoftheneuralstemprogenitorcells(NSCs)whichoccursinaregioncalledtheSGZ,whichisroughlydefinedasatwocelldiameterbandoccurringonthehilussideofthegranulecelllayer(GCL)ThesecondphaseisthesurvivaloftheproliferatingNSCsDuringthisphase,thenumberofsurvivingneuronscanvarygreatlydependingonthestrainofanimalsusedandcanbeasgreatas~orasfewasoftheamountofproliferatingcellsThethirdphase,occurringinconcertwiththesecondphase,isthedifferentiationofthenewlyborncellsInthisphase,themajorityofcellsdobecomeneurons,withasmallerpercentagebecomingastrocytesandoligodendrocytesThefourthphaseinvolvesmigrationoftheneuronsintotheGCL,withmostofthemigrationoccurringaroundthefirstweekFinally,thefifthphaseinvolvesthefunctionalmaturationoftheneuronsintheGCLwhichoccursaroundweeksofage,butsomecellsmaytakeweeksorevenmonthslongertofullymatureIthasalsobeendemonstratedthatthoseadultbornneuronsthatsurviveafterweekswilllikelybepresentatleastmonthslaterThemajorityofthedecreaseinneurogenesiswithageappearstooccurmostlyinthefirstphasewherethereisadecreaseinproliferationwithadvancedageSurvivalofthenewlyborncellsappearstobeunaffectedbyage,whilematurationofthecellsparticularlyindevelopingamatureneuronalphenotypeandmigratingintotheGCLdoesseemtobeaffectedbyageBeyondthelimitedeffectofsynapticplasticityinthetwogerminalcentersinthebrain,neurogenesisfromendogenousNSCmayprovideanalternativetotransplantationofstemcellsasameanstoreplacedamagedneuraltissueafterbraininjury,suchasstroke,orasaresultofaneurodegenerativeconditionAgrowingbodyofresearchshowsthatneurogenesismayoccurinldquononneurogenicrdquoregionsasaresultofastrokeorneurodegenerativediseaseThereisalsothehopeofrecruitingNSCsfromtheneurogenicregionsofthebraintoreplacedamagedcellsafterinjuryBeforeeitherstrategyofusingneurogenesisasatherapeuticsourceofnewcellscanbeimplemented,abetterunderstandingoftheregulationofneurogenesisisnecessaryInmanypathologicalconditions,includingADandPD,neurogenesisisdramaticallyaffectedbythepathologyndashNeurogenesisshowsasignificantdecreaseInterventionsinAgingandNeurodegenerativeDisease:EffectsonAdultStemCellswithagendashThemajorityofthesuppressionofneurogenesiswithageappearsnottobeNSCsautonomousbutismoreafunctionofthemicroenvironment,asanynumberofenvironmentalalterationscanincreaseordecreaseneurogenesis(reviewedin)Furthermore,thepoolofNSCappearstobeintactwithrespecttothetotalnumbersofavailablecells,providingmoreevidencethatthattheneurogenicnicheisatleastpartlyresponsibleforthedecreaseinneurogenesiswithageThatcellularsenescenceoccurswithagehasbeenknownsincethes,buttheimportanceofthecellularsenescencewithintheagednichehasonlyrecentlybecomeanareaofactiveinterestAclearexampleoftheimportanceoftheextrinsicorsystemicinfluenceonthestemcellnichewasdemonstratedinthestemcellsthatarefoundinthemuscle,calledsatellitecellsLiketheNSCs,thesatellitecellsinthemusclelosethepotentialtoregeneratedamagedtissuewithageInanelegantexperiment,whenagedratswereexposedtothesystemicenvironmentofayoungratbyparabiosis,thesatellitecellswererejuvenatedintheagedratsasdemonstratedbyanincreaseintheproliferationrateConversely,inyoungrats,theexposuretothecirculationoftheagedratscausedadecreaseintheregenerativepotentialofthesatellitecells,againsupportiveofanextrinsiccirculatingfactorthatisinfluencingtheproliferationofthestemcellsintheagedanimalsItisnotclearwhetherthemechanisminvolvedintheeffectinthemusclewouldholdtrueinthebrain,buttheimplicationisthattheagedenvironmentisdetrimentaltostemcellfunctionThisalsoholdstrueforeventhemostpluripotentofstemcells:theembryonicstemcellsWhenembryonicstemcellsaretransplantedintoagedtissuetheyarenotabletorepairdamagedtissueaswellaswhentransplantedintoyoungtissueTheseaforementionedexamplesdemonstratetheimportanceofunderstatingthebiologyoftheagedstemcellnicheandmayprovideinsightintowhysomeoftheclinicaltrialswhichusedcelltransplantationforneurodegenerativediseasehavenotbeenaseffectiveaswashopedThus,itappearsthatforastemcellbasedtherapytobecomeefficacious,abetterunderstandingoftheagednicheandhowthenicheregulatesthestemcellpotentialwillbenecessaryAmultitudeofchangesthatoccurtothemicroenvironmentoftheagednichemayberelatedtothedecreaseinneurogenesisOnepotentialchangeisadecreaseinanumberoftrophicfactorsincludingBDNF,VEGF,IGF,andFGF,ThereisalsoanincreaseincorticosteroidlevelswithageAhallmarkofagingaswellasADandPDisanincreaseininflammationWhilealossoftrophicfactorsandincreasedcorticosteroidsareimportantcontributestotheagednicheandhavebeenextensivelyreviewed,thefocusofthischapterislimitedtotheroleofinflammationinregulatingstemcellfunctionintheagednicheNeuroinflammationinAgingandDiseaseInflammationisanactiveprocesswiththepurposeofremovingorinactivatingpotentiallydamagingagentsFollowingremovaloftheldquodangersignal,rdquoasecondpathwayisinitiatedwiththeroleoftissueremodelingInthecentralnervousADBachstetteretalsystem(CNS),theinflammatoryprocessmustbewellcontrolledSinceamajorityoftheCNSlacksthepotentialtoreplacelostcells,aninflammatoryinsultcouldbedevastating,resultinginneuraltissuelossIngeneral,inflammationisagoodthingwiththeprimaryresultofremovingthenoxiousagentandremodelingtheadjacenttissueWheninflammationisnotwellregulatedfollowingresponsetoldquodangersignals,rdquoachronicpathologywillresultItisknownthatwithagingandagerelatedneurodegenerativediseases,namely,ADandPD,thereisastateofchronicinflammationThecauseofthechronicinflammationinagingisnotclearItwasinitiallybelievedthatinAD,inflammationwasexacerbatingthediseaseAsurprisingexperimentinducinginflammationinamousemodelofamyloidpathologythroughtheuseoflipopolysaccharideresultedinaparadoxicalreductioninamyloidbTheseresultsseemtocontradictthecommonhypothesisthatchronicinflammationispartofthediseaseprogressionThiscontradictioncomesfromashortcomingintheinflammationhypothesis,namely,inflammationisanegativethatshouldbeeliminatedTheimmunesystemisnotamistakeofevolutionThemajorityoftimetheimmunesystemprotectsusfromourenvironmentIntheCNS,theimmuneresponsehastobewellcontrolledfortheresponsetobebeneficialTworecentexamplesofthebeneficialroleoftheimmunesystemweredemonstratedinananimalmodelofPDInthefirstexperiment(Figaandb),ratswerefedadietenrichedwithblueberryorSpirulinapriortoahydroxydopamine(OHDA)lesionAtweekafterthelesion,alltheanimalsirrespectiveofdiethadasimilarlesionvolumeAtweeksafterthelesion,theanimalsthatwerefedthedietenrichedwithblueberryorSpirulinahadasignificantreductioninthesizeofthelesionThesurprisingresultwastheimprovedrecoveryatweeksafterthelesionmayhavebeenduetoamorerobustimmuneresponseatweekafterthelesionAsshowninFigb,ratsontheblueberryorSpirulinadietshadasignificantincreaseinthenumberofactivatedmicrogliaatweekafterthelesionandthiswasfollowedbyasignificantdecreaseinmicrogliaactivationatweeksafterthelesionTheseresultssuggestthatarobustearlymicrogliaresponseisbeneficialinremovingthedeadanddyingcellsandremodelingtheremainingtissueInafollowupexperiment(Figcandd),theimmediateimmuneresponseversusthechronicresponsewasclearlyelucidatedTumornecrosisfactora(TNFa)isakeyproinflammatorycytokinethatisproducedbyavarietyofcelltypesbutinPDpatientsisparticularlyassociatedwithactivatedmicrogliaUsingthesameratmodelofPDasthepreviousexperiment,anantisenseTNFspecificoligodeoxyribonucleotidewasgiveneitherimmediatelyaftertheinsultorbeginningdaysaftertheinsultBlockadeofimmediateTNFaeffectswasdetrimental,butblockingtheproductionofTNFaatthelatertimepointwasbeneficial(Figc)Aswasseenwiththedietsupplementationstudy,theearlyactivationoftheimmuneresponseappearstobenecessaryandbeneficial,whereasastateofchronicinflammationisdetrimentalOnewayinwhichchronicinflammationisdetrimentaltotissueremodelingafterinjuryisbydecreasingtheregenerativepotentialofstemcellsTwoseminalstudiesanumberofyearsagoshowedthatinflammationtightlyregulatesInterventionsinAgingandNeurodegenerativeDisease:EffectsonAdultStemCellsneurogenesis,Sincethesestudies,anumberoflaboratorieshavebeeninterestedinhowinflammationregulatesneurogenesisTheresultsarefairlyclearandreproducible,namelyneuroinflammationwillresultindiminishedneurogenesis,anddecreasingtheneuroinflammationwillrestoreneurogenesisWhatisnotclearishowinflammationregulatesneurogenesisFigNeuroinflammationisprotectiveaftertoxicinsultiftheresponseiswellcontrolledaFollowingahydroxydopamine(OHDA)lesioninthestriatum,alossoftyrosinehydroxylase(TH)immunoreactivitywasseeninalllesionedanimalsatweekAtweeksafterthelesion,asignificantreductioninlesionvolumewasfoundinthoseratsthatweretreatedwiththeblueberryorSpirulinaenricheddietsbTheprotectiveeffectatweeksinratsthatwerefedablueberryorSpirulinaenricheddietmayhavebeenduetoamorerobustearlymicrogliaresponseatweek,asdeterminedbythenumberofOXpositivemicrogliaTheearlymicrogliaresponseatweekwasfollowedbyareturntononlesionsnumbersofOXpositivemicrogliaintheenricheddietgroupsatweekscWhenanearlyimmuneresponsewasblockedbyatumornecrosisfactora(TNFa)antisenseforthefirstdaysafterthelesion,alargerlesionvolumewasfoundcomparetothecontrolHowever,inhibitingTNFafordaysstartingdaysafterthelesionresultedinabeneficialeffectdAreductioninOXpositivemicrogliawasfoundintheTNFaantisensetreatedanimalsThedecreaseinmicrogliabyTNFaantisenseduringthefirstdaysfollowingthelesionmayhaveblockedtheearlymicrogliaresponsewhichwasfoundtobeprotectiveintheanimalsfedablueberryorSpirulinaenricheddietHowever,blockingTNFaduringdaysndashappearedtostopthechronicinflammatoryresponsewhichwaslikelydetrimentalinthecontrolratsthatdidnotreceivetheTNFaantisenseortheenricheddiets*P,**P,and***PADBachstetteretalTheRoleofCytokinesinRegulatingNeurogenesisInterplaybetweentheimmunesystemandtheCNSunderliesmanyoftheneurophysiologicalchangesthatoccurwithagingCytokinesareaclassofpolypeptidesexpressedatlowlevelsinhealthytissuethatarerapidlyinducedinresponsetotraumaorimmunechallengeLevelsofspecificcytokinesexpressedinthebrainincreaseasafunctionofage,evenintheabsenceofapathologicalstimulusForexample,thereisaprogressiveincreaseintheexpressionofinterleukin(IL)andmicrogliaactivationwithaginginneurologicallyintactpatients,ILlevelsalsoincreaseinthemousebrainwithadvancingageInthecerebellumofagedrats,tumornecrosisfactora(TNFa)geneexpressionisdramaticallyincreasedcomparedtoyoungrats,andthisincreaseispreventedbyadietrichinantioxidantsImmuneresponserelatedmoleculesandtheirreceptorsareexpressedthroughoutthebrain,andrecentresearchsuggeststhatbrainderivedimmunefactorsdisruptnormalphysiologyandcontributetocognitiveandbehavioraldysfunctioninneurologicaldiseasendashILbisoneofthemaininflammatorycytokinesfoundintheCNSILbisconstitutivelyexpressedinthebrain,synthesizedbyneuronalandorglialcells,andreleasedinresponsetoavarietyofstimuli,includingimmunesystemactivation,ILbisaproinflammatorycytokineinitiallysynthesizedasaninactiveprecursorthatiscleavedbycaspasetogeneratethebiologicallymaturekDaformILbaffectsvirtuallyeverycelltypebybindingtoahighaffinityreceptor,ILRI,TheILbreceptorexpressionishighinthehippocampusasindicatedbybindingstudies,TheILfamilycomprisesthreeknownligands:ILa,ILb,andILraThebiologicalactivityofILbisdependentonitsinteractionwithILRIandrecruitmentoftheILreceptoraccessoryprotein(ILRacp)ILrabindstoILRIbailstoassociatewithILRacp,therebyactingasahighlyselectivecompetitivereceptorinhibitorTheonlyknownfunctionofILraistopreventthebiologicalactivityofILThepotentialroleofILbinthemediationofanagerelatedreductioninneurogenesisandlearningandmemoryhasbeenexaminedInonestudy,thenonsteroidalantiinflammatorydrug(NSAID)sulindacwasadministeredtoagedratsInthisstudy,wefoundthatsulindactreatmentresultedinadeclineinILblevelsandareversalintheagerelateddeficitsinradialarmwatermazeperformanceandcontextualfearconditioning(Figa)InasecondexperimenttodetermineifILbisinvolvedinthereversalofagerelatedcognitivedeficits,weusedanenzymaticinhibitorofcaspaseCaspasecleavesimmatureILbtoproducethemature,activeformThecaspaseinhibitorAcYVADCMKwasgivenfordaysviaanosmoticminipumpintotheleftlateralventricletomontholdandmontholdmaleFischerratsAfterdaysofcaspaseinhibition,theratsweretrainedinthecontextualfearconditioningtaskOnday,theyweretestedforthehippocampusdependentformofmemoryUsingthecaspaseinhibitor,wefoundasimilarimprovementinthememorytestaswasseenwiththeNSAID(Figb)Inafollowupexperiment,wehypothesizedthatthecaspaseinhibitionmaybeimprovinghippocampaldependentmemorybyreversingtheagerelateddeclineInterventionsinAgingandNeurodegenerativeDisease:EffectsonAdultStemCellsinneurogenesisFollowingthesameexperimentalmethodsasthepreviousstudy,wefoundthatcaspaseinhibitiondidresultinanincreaseinneurogenesisintheagedrats(Fig)AsexpectedcaspaseinhibitiondramaticallyreducedILblevels,buttheeffectwasnotlimitedtoILbInaddition,caspaseinhibitionalsodecreasedTNFaandmicrogliaactivationFurthermore,therewasalsoincreaseintheantiinflammatorycytokinesIL,aswellasanincreaseinIGF,SowhilethetargetforcaspaseinhibitionwastodecreaseILblevels,manyinflammatorypathwayswerealteredbycaspaseinhibitionThisisinpartduetotheinterdependencyofthecytokinesandtheircascadingeffectNevertheless,ithasbeenshownthattheNSCsdoexpressthereceptorsforbothILbandTNFa,therebyhavingthepotentialtoeffectproliferation,development,orsurvivaloftheNSCndashILbisapotentsuppressorofneurogenesisbutitisnotcompletelyclearhowILbachievesthiseffectILbisabletoinduceapoptosisinNPCphosphorylationoftheSAPKJNKpathway,therebyhavingadirecteffectonthesurvivalofthenewbornneuronsTheNFkBIkkpathwayalsoseemstobecriticalinregulatingtheeffectsofILbonproliferation,possiblybydecreasingcyclinDexpressionILbalsoseemedtoslightlyfavordifferentiationintoanastrocytelinageasdeterminedbythemarkerGFAPFigAgerelatedchronicneuroinflammationimpairscognitivefunctionDecreasedneuroinflammationintheagedbrainbyanonsteroidalantiinflammatorydrug(NSAID)(a)orcaspaseinhibitor(b)restoredcognitivefunctioninagedratsaSulindac,anNSAIDthatisanonselectivecyclooxygenase(COX)inhibitor,wasshowntoreversetheagerelateddeficitsincontextualfearconationinmontholdmalefisherrats,whilesulfoneanonCOXactivemetabolitewasnotabletoTheimprovementinmemorywascorrelatedwiththereductionininterleukin(IL)bTherewasnoagerelatedeffectonfreezingtothenovelcontext**Pfromyoung,daggerPfromagedcontrol,andDaggerPfromagedsulindacbUsingacaspaseinhibitorwhichblockstheformationofactiveILbresultedinasimilarreversalofagerelateddeficitsincontextualfearastheNSAIDtreatment*PADBachstetteretalFigAgerelatedneuroinflammationcausesadecreaseinhippocampalneurogenesisaAgingresultsinasignificantdecreaseinneurogenesis,aswasseenbythedecreaseinBrdUpostivecellsinthesubgranularzonegranulecelllayer(SGZGCL)ofagedfisherratscomparetoyoungadultratsTheagerelateddecreaseinneurogenesiswasattenuatedbydaysofintracerebroventricularinfusionofAcYVADCMK,acapaseinhibitor(*P)CaspaseinhibitionblockstheproductionofproILbtotheactiveformofinterleukin(IL)bTheresultsdemonstratethatatleastpartofthedecreaseinhippocampusneurogenesiswithageisduetoelevatedcytokinelevelsRepresentativeconfocalmicrographof(b)BrdUlabeledcells(red)andNeuN(green)and(c)BrdU(red)andTUJ(green),confirmsthattheincreaseinBrdUcellsdidrepresentanincreaseinneurogenesis(SeeColorPlates)InterventionsinAgingandNeurodegenerativeDisease:EffectsonAdultStemCellsILbisnotaloneinbeingabletodirectlyaffectNSCRecently,Iosif()hasshownthattheinflammatorycytokineTNFacanalsoassertadirecteffectonNSCproliferationTNFreceptor(TNFR)appearstohavearegulatoryfunctionbyblockingproliferationduringinflammationThisactionoccursdirectlyattheNSCswhichexpressbothTNFRandTNFRTNFRappearstoplayaneuroprotectiverole,althoughitsfunctionisalittlelessclearthanthatofTNFREffectonMicrogliaThemaincelltypeintheCNSthatisresponsibleforimmunityisthemicrogliaWhileastrocytesandneuronscanmakeinflammatorymediators,themicrogliaarethemainsourceofinflammatorycytokinesMicrogliaarealwayssurveyingthemicroenvironment,andoncetheysensetheappropriatequeuessuchasneuronaldamage,thecellswillhonetothesiteofdamageThisinitialphaseofactivationappearstobeverybeneficialinprotectingthebrain,butiftheactivationcontinuesunabatedthenmoredamagecanresultItappearsthatthiseffectisduetothedelicatenatureoftheCNSandneuronsrsquoinabilitytoregenerateinmostregionsofthebrainAstheresidentimmunecellsintheCNS,microgliaconstitutivelyexpresssurfacereceptorsthattriggeroramplifytheinnateimmuneresponse,includingTolllikereceptors,complementreceptors,cytokinereceptors,chemokinereceptors,majorhistocompatibilitycomplexII,andothersHowever,theroleofmicrogliaisnotdestructiveUpondetectionofhomeostaticdisturbance,microgliarapidlyrespondbyinducingaprotectiveimmuneresponseTheprotectiveimmuneresponsebeginswithatransientupregulationofinflammatorymolecules,includingproinflammatorycytokinessuchasTNF,IL,andIL,andIL,ThisisfollowedbyaprotectivephasethatisimmunomodulatoryandneuroprotectiveTheprotectivephaseincludesneurotrophicfactorssuchasBDNF,GD

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