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Chapter6Stemcells
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Howarethebillionsofourbodiesmade?Inplantsandanimals，therearecellscapableeverytypeofwillneedfrombirthtodeath.aomature，othercellsarerequiredtoprodugeofspecializedeededforafunganortissue.Suchcellsareknownasstemcells.Asteologyhasdevelopedandthemicro-disseoftissuebecamepossible，itwasevidentthatmost，ifnansahebodyhavetheirownstemcellsableofdividingaingiionalsomeways，stembeimaginedasblahmanyhiddencellularpicturesalreadyimpriheDifferentbinatirowthfactors）orotherstimulisuchasfatsarsthattouchthestimulatedivisionandallowthedaughtercellstotakeoeristithischapterwelookbrieflyatthetypesofstemdwherethey.
Iherearetesofstemcells—embryonidadult（Figure 16）.Embryonicstemcellshavedifferentbiologicalpropertiestotheadultstemcellsthatarefouoah，hatinatioypeofstemdevelopmee，producedbythefusionofeggandsperm，whichhastheplete‘poteeeverytissueaypeinthebody（apropertytermed‘totipotent’）.Astheembryogrows，‘pluripotent’stemcellsappear，whicharelimitediency.ThesecellsdivideaeintothemainclassesofESownasthegermlayersinmammals）auransandtissues.Fromembryotoadult，ourcellulargrowthrelieson:‘multipotegiverise，afterdivisionaioypesbelongiedcellfamily;‘oligopotehataremorelimitedstill，produgjustahandfulofcloselyrelatedplemyeloidbloodd‘uemcellsthatwillgiverisetooype，forexamplemusclecells.Thetermprenitorstemcellisofteodescribethosecellsstillrapidlydividingbutfullydiffereprogenitorstemcellsrepairtissuesbyprodugspecificcelltypesomaintainnormalturneiveans.
16.Theinsofembryonidadultstemcells
Beforeweuethestoryofstemedevelopmentsieeedtobedescribedastheyhavegreatlyacceleratedeofthisarea.First，therewastheserendipitousdiscoveryofthepresenceofspecifisandsugarmolethesurfaceofvarioustypesofstemcells.
Ahesemoleculeshaveaccuratelycharacterizedstemcellpopulations.Seethodcalledfluorestactivatedcells（FACS）usesfluorestlytaggedantibodies，whichallowliviobemeicallysortedagtotheirsurfas.Ihesuspensionofcellsismixedarticularfluorestibodyahroughaverynarrowtubeilluminatedbyabeamht;alight-seectsthosecellsthatproduceaflulow.Thepositivebeanalysedorcolleixtureusiicdefieofthefluorestmicro-dropletsastheyemergefromthetube.Usiypesofantibodybutnowattaaghepartiallypurifiedstembeisolatedinumberforicaluse.Cellpopulationsalsobefollowedaftertransfusionibyattagasmallgreeproteiooseionsofthisjellyfishproteingeneproduydifferectolightofspecifigthsforaalysis）.Whehisgeneisexpressed，itsproteinfluoressidethecells.Similar‘biolumieologyhasbeeoseeindividualcellswithinthelivinganimal，oftenusiivecamerasinallydevelopedforsatellitesurveillance.
Historicalperspective
Igwomillennia，Aristotle，inhisbook OionofAnimals，firstproposedthetheenesisinbiology，suggestiofaplantoranimalfromaneggorsporefollowsasequeepsinwhidthevariansfhthistheorynowseemsobviousiicage，itwasnotgivenmucebeiionistaionisttheoriesoflife’sinsformauries.In1795theembryologistCasparFriedriouslyrefutedpreformationisminfavenesis.Aendedandtroversialdebatebybiologistsfinallyledepigeheloablishedpreformationistview.Visualuandingofcellpopulationsuedwithimprovementsinmicroscopy.Attheturhtury，Ernsthethebonemarrowa
Thedifferentformsofallbloodcellshappenihelymph-ansandinthebonemarrowarealldestsofthe‘great-lymphocytic’stemwhichwaythisstempletesitselfagainandagaiherexclusivelybyamitotioralsofromothercells.
Thisrobablythefirstuseofthetermstemcell.
Embryonicstemcells
Stemdintheembryogiverisetenumberofcellstogeeall200ofthecelltypesinthehumanbody.Inhumans，theinnercellmass（see Figure 17）oftheearlyembryohas50–150cellsofthreeprimarytypes.In1981，MartinEvansandMatthewKaufmaeiquefortheouseembryosaionofculturedembryonies.Laterthatyear，GailMartinfirstusedtheterm‘embryoodescribethesees.Eightyearslater，JamesThomsonisolatedagroupoftheinnercellmassoftheearlyhumanembryoaablishedthefirstembryoniesiheanyhumanembryonicstemcellsarisesfrom iion（IVF）procedures.
Whilesharingmanysimilarbiologicalproperties，mouseandhumanembryonicstemcells（EScells）requiredifferenteheirsustaihwithoutdifferentiationinplasticflasks.Forexample，mouseEScellsgrowelatinaheadditioeingrowthfactorLIF，whereassimilarhumanesrequireafeederlayeroflivemousefibroblastdahfaanfibroblastgrowthfactor）.Withoutoptimalgrowths，thecellsstopdividingandrapidlydifferehegrowthofvariousESeshasuhereisaninguandingofthegenesinvolvedinmaintainingstemcellcharacteristics.Themaintenanceofpluripotencyrequiresaregulatoryhatehesuppressioleadtodifferentiatiouationistolimitdivisionandtodiffereurehasperhapsevolvedanalmostfoolproofmeismtoprotefromthedahatevadethenormaltrolsongrowth.
Germ-liemeratesperms（haploidgametes）whichhavehalfthenormalnumberofes，andtraiatieothe.Suchcellsareeasilyiderieved，andmahefruitfly.Intheseflies，eggsdevelop（orovariole）withintheflyovary.Atoneend，asmallnumberofgerm-liemcellsmovealongatapredictablerateaeihidays.Thestemcellsaresurrouhreediffereypes—termicells，capdihcells—whichhelpmakeupananatomicallysimpletubularstructure（germarium）.Thecellsatthetipoftheovariaoamaintainsandtrolsthegerm-liemcells.Aspecialcell–edbetweeemahesejun-liheanteriorafrommovingawaywhereitmightreceivedifferentiationcues.Aspealproteiomaintainthisjundtrerm-liemcelldivision.
Inplants，allstemcellsaretotipoteodivideaeintoallthecelltypesoprodutireanisTotipotentwasatermiheAustrianbotanistGottliebHaberlandttodescribeapropertyknowntoallgardenerswhohaveformillenniaplacedsmallpartsofaplantsuchasleaves，stems，androotsintosoilaoprocreatetheirprecioussthgs.Thefirstgrowthofanindividualplantcellbae（acarrot）erformedbyFredStewardie1950s.Mouse-earedcress，Arabidopsisthaliana，isamuch-studiedsmallflplantusefulfeudies.Thegrowingtipisapletelyuissuefouhatuestomakeleaves，flowers，ahroughoutaplahe30–40stemcellsthatresideinthisplexstructurearesurroundedbymillionscells，makingthisaodeltostudy.Mostgeshaveresortedtousingroottips，whicharelessplex.Byusingamutantthatproducesahighnumberofaccessibleshootmeristems（embryonictissue），ageneexpressionmaphasbeehemeristemthathasallowedthecharacterizationafluorestmarkingoftheseelusivestemcells.
Adultstemcells
Historically，ofstemcellsbeganwithobservationsofhowadultstemeratevasturedaughterstNeumann’sfar-sightedideasintheareaofbloodproduthebonemarrowdemahephysicalpletiohisproofwasnottoarriveuerwhenresearchersdiscoveredvariouspartsofthisplexpuzzle，showingthatstemthebonemarrowcouldselfrenewaswellasdividingandprovidingallthevariousmatureblood.
IMcdJamesTilldevisedaseriesofexperimentsthatiingbonemarrowtothetailveiedfrtheirownstemcellsbyalethaldoseofX-rays.Visiblenoduleswererowihemidthesewereinproportiontothenumberofbonemarrowjected.McdTillspeculatedthateaodulearlemarrowcell，probablyastemcell.Thisanimal-basedmeasureofbonemarrowstemcellsprovidedthemajortoolfstemumbersfortheheearly1970s，MikeDextershowedthatitossibletogrowprimitivebonemarrowanyweeksinlaboratorycultureflasksiftheyhadastromalcellfeederlayer（thisisavariedofnoypespresentinthebonemarrow）.
Ihatfollowedmaissue-specificadultstemcellshavebeeified.Thesestemcellsareallcapableofdivisionaionintothepoypesoftheirrespectivetissue.Therowthofnewneuronsinratshassuggestedtheexisteemtheadultbrain.Thisiiionreviousideasthatbraiedalifetime.Siemcellshavebeeedinthebrainsofadultmigbirds，andprimatesinghumahofnewneuronalownasneurogenesis）isrestrictedtotwolothebraiembegroworyasfloatingcellaggregates（alargeemcells.Bygthecultures，theybediffereobothricallyexcitablecellsthatprodtransmitinformation）andglia（cellsthatfeedahebrain’sneurons）.
aemcellpopulationsthatsupplythematurecellsrequiredeitheruouslyoratspecificstagesofdevelopment.Examplesiemcellsthatarethesourceofmaryglandduriheyhavebeenisolatedfrombothhumanaissueand，inculture，differeolumiheientiallymilk-produgdmyoepithelialcells（theouterlayer）aswellashaviyteireaninthemouse.HumanolfactoryadultstembeharvestedfrommucosatheliningoftheherlikeEScells，theydiffereeofcelltypesandareseenasapoteicsourcebecauseoftheease，espeolderpeople.Hairfollitaiypesofstemdtheygiverisetoneurons（nervecells），Scells（whitributetothemyelih），myofibroblasts（acrossbetweenfibroblastandsmoothmusclecellsimportantinwoundhealing），drocytes（cellsthatmakeandmaintaincartilage），aes（melanin-produgcellsthatgiveyouasuntan）.Basalcellsmakeupabout30%oftheepitheliumofthelungand，inhumathroughouttheairways.Theyarerelativelyuedandprobablyactasastemcellforthistissue.Furtheruandingiayleadtotheiruseiion.Theproblihelialtothebloodvesselliningmainlyembryo.Initially，itwasthoughtthatthesecellswerederivedfromendothelialprogenitorstemcellsearlyi，butinthe1990sputativeadulteemcellswereidentifiedinadultmouseblood.Retweststhatadultendothelialprogenitorcellsareimportaionofbloodvessels，especiallywhennewbloodvesselgrowthisrequired（aed）byagrowingtumour.Endothelialprogenitorstemcells，likebloodstemcells，areretotheblrowthfaiumoursite.Destruofthesecellswithinthebonemarrowreducethegrowthrateofatumour，asnotumourueterthantwomillimetresiabloodsupply.
Stemcellproperties
Adultstemumbersremainasaallpoolofcellswithiissue.Giventheirpropensitytodivide，anyestrolcouldbefataltotheanimalorplaherhand，eaeedstoreselfaslyihtercellscapableoffurtherrapiddivisionaiohemillionsofeededforafunalanortissue.Toexplainthisobservationinbonemarrow，RaySchofieldproposedthehypothesisthatstemcellsexistinaspecializedsiteorhisniposedofagroupofcellsdedicatedtotheprovisionofamieenanceofasiemcell（Figure 17）.ionasa‘basewhichstemcellsarephysicallyretaiingasalastingreservoirfortissueregeithebalaweenself-renewalaion，thenicheplaysaialroleingstemcellfateandmaintainingstemumbers.Inmostcases，adultstemcellsretaiheesaredormantuntiltheyrealsfromthemientthatstimulatestemcelldivision.Whatstitutesthissignalstillremainsunedaughtercellremainsintheemcellwhiletheother，whigerfitsintheniche，leavesahroughrapiddivisionaiontoformmaturecells.Ifthemientisfurtherstimulated，suchasbyapplyingagrproteieofthisprobegreatlyaccelerated.Thenichemodelhasbeenshownacrossavarietyofstemcellstudiesiemssutheovariesofflies，plants，andintheials.Whetherthissimplemodelisuoallstemcellsremainsunclear.
17.Asimplemodelofthestemiche.Thetheniantuimulifullyuood.Followingdivision，thesoercellwhiletheother，nenitorstemcell，dividesmanytimesaomillionsoffullydifferentiatedcells
Adultstemcellshavethecharacteristicofplasticityortraionwhiverysimpleterms，meansthatoypederdifferents，turniype.Forexample，inmi，embryoniarrow，adultliverprogenitor，aemallproducematurecellsoftheliver.Thesegesbeperformediorybyintroduggroroteiemcellsorbytransplaotheliverwheretheyareabletorepopulateand，insomecases，evenimproveliverfun.
Iherearethreeprimarygermlayercelltypes:e（givihenervoussystem，toothenamel，hair，aesoftheskin），endoderm（developingis，respiratorysystem，andbladder），andmesoderm（responsibleforboivetissue，themiddlelayeroftheskin，liver，andbonemarrly，allthreeofthesecelltypeshavebeenfoundtoproducematureallyderivedfromadifferentlineage.
Whatisnotclearishowthistraionofstemcellsworks.Thefateofthestemcellisdefibyitsgeicprofileatdivisionbutalsobytheexternalsignalsitreceives.Ifhitbyfiigexternalsignals，theswiteticprofileaoadiffereype.Becausetheyarerelativelysmallandstructurallyindistinct，thevisualidentifioftrueadultstemcellshasalroveddifficult.Ithasbeeplasticitycouldbeexplaihepresewoormorepopulationsofstemcellswithiissue.Forexample，adultstemcellsgiverisetomaturecelltypes，whileasmallernumberofgermstemcellsarestillabletoproduceallcelltypes.Ahattriestoexplainthebalaweenselfreemdthinthebonemarrow，hairfollidthegut，proposesthatastemexistintwodifferentstates.Oneisdormant，astemcellretainingafulldevelopmeial，whereastheotherstemcellsareactive，capablelargenumbersofdifferehebalaiveaemcellsistrolledbythelevelsofvariousdevelopmentalsignallingproteinswhichwerefirstidentifiedinfruitfliesbutnowkoallanimalcells.
abolicactivities—espeArepli，wheheorssuchasicchemicals，UVlight，andradiation—Adamage.Itiscalculatedthatasmanyasonemillionindividualmolecularlesionspercellperdayoccur.ThecellhasaofprocessesbywhichthesedamagedDsareidentifiedaoftheseDNAgesareharmless，andsomeprobablytributetowhywearealldifferent.SomecauseseriousstructuraldamagetotheDNAmoledaltertheabilityofthecelltosurvive.ExamplesoftheselethalcludethechemicalkingeoftheDNAstrands.FailureofthenormalprocessesofDNArepairisreizediheproteiionediheeitherslipsistateofdormanassenesceordiesbyapoptosis.Intheabsenceofap53respohedamagedcellmaybegintountrolledcelldivisiinacer.
Allanimalcellshaveaninternalageingclock.Everyehasprotectivestructuresateadcalledtelomeres，whicharemadeupofrepeatsoftheDAGGG.Telainsttheendsofesfusiheformaties.Eachtimethecelldivides，owocopiesofthissequereplatually，aftermanydivisions，thisproteattelinstorunoutandtheeeo‘fray’，atwhitdivisionceases.Embryonicstemcellsavoidthislimitationonthenumbersof‘permitted’divisiaelomerasethatrepairsthedamageandallowsforthemultipledivisionsrequiredi.Inadulttissue，cellsthatodivideuously（forexampleimmunedaemcells）alsohavehighlevelsoftelomerase，whereasmostothercelltypesexpressitatlowlevels.Highlevelsoftelomeraseareoftenfoundinrapidlydividingtumourcells.
&emcellsatthegrowingtipsofplaivethroughoutlife，whichmaybeturiesirees，duringwhichtimetheyaretlyexposedtoealhazardsthatAdamageandmutations.AllplantshavemeismsthatrespondwithgreatsensitivitytoDherfromradiationoridsignalah.Similarobservationshavebeenmadeinmousebonemarrowstemcells.Theevolutionofthisstriwaytheirgeyinthesecrucialcellpopulationsisdistinalprogrammedcelldeath.Ohereisanobserveddethenumbersofadultstemmanymammaliaime，prfromgraduallow-levelDhisaffectstheirabilitytodivideushioadormaheemichesmayalsodecrease.Wegrowoldbecellsageasaresultofmeismsthatinouryrowthofcercells.
&emcells
Theideaofcerstemcellshasslowlyincredibilityoverthelastteheleukaemiastemcellwasthefirstsuchcelltobedescribedbutithasbeecersofthebrain，，ovary，pandprostatemayalsohavestemcells.Theinsofthesecellsaretroversial.Theceptisbasedohat，aswithnormalstemcells，apoolofmaligheabilitytoielyselfreetumoursindistantlos.Aswithnormalstemcells，theselydivideslowly（inotherwordsselfrenew），whichmakesthemmoreresistanttoahatusuallykillrapidlydividingcells，whiletheirdiffereercellsremaiive.Oionofleukaemiastemcellsisthatthegeicdamageleadingtocertakesplaewlydifferentiatedcellfollowedbyade-differeriggeredbythestemiche，resultiedbutimmortalsupplyofleukaemicstemsolidtumoursitisextremelydifficulttopinpointthepreciseiivecerstemcellasthetumourhasaheterogeneouspopulationofmutantcells.Amoheremaybeseveraltypesofstemaltothespeviroandseverallesssuccessfullierbeoresucsomees，allowiofurtheradapttoitse.Ongoingstemcellresearchmayhaverepersonment.
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