Chapter 6 Stem cells（第1页）

Chapter6Stemcells

Howarethebillionsofourbodiesmade?Inplantsandanimals，therearecellscapableeverytypeofwillneedfrombirthtodeath。aomature，othercellsarerequiredtoprodugeofspecializedeededforafunganortissue。Suchcellsareknownasstemcells。Asteologyhasdevelopedandthemicro-disseoftissuebecamepossible，itwasevidentthatmost，ifnansahebodyhavetheirownstemcellsableofdividingaingiionalsomeways，stembeimaginedasblahmanyhiddencellularpicturesalreadyimprihem。Differentbinatirowthfactors）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，allstemcellsaretotipoteodivideaeintoallthecelltypesoprodutireanism。TotipotentwasatermiheAustrianbotanistGottliebHaberlandttodescribeapropertyknowntoallgardenerswhohaveformillenniaplacedsmallpartsofaplantsuchasleaves，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。