Lecture1HematopoiesisIntroductionOntogenyofhematopoiesisDescriptionoftheHematopoieticStem Cell(HSC)TheconceptofthestemcellnicheAnatomicaldescriptionofthe stem cell nicheFunctionaldescriptionofthestemcellnicheRoleoflineage-specificGrowthFactorsinhematopoiesisTheformationofmaturebloodelements:1.MyelopoiesisErythrocytesGranulocytesPlateletsTheformationofmaturebloodelements:2.Lymphopoiesis.Tcells.Bcells3.NKcellsBoneMarrowFailureheriteddisorders2.AcquireddisordersIntroductionTheformedelementsoftheblood,suchasredcells,whitecellsandplatelets,playavitalroleinthenormalfunctioningofanyhumanbeing.Theyaretheendproductofahighlyspecializedtissuecalledthebonemarrow,whichresidesinthecavitiesofallbonesofthebody.TheprocessthroughwhichformedelementsofthebloodareproducediscalledHematopoiesis.Hematopoiesiscanbeenvisionedasahierarchicalprogressionofmultipotentialhematopoieticstemcellsthatgraduallyloseoneormoredevelopmentaloptions.Theythenbecomestemorprogenitorcellscommittedtoasinglelineage.Thesesinglelineageprogenitorcellsthenmatureintothecorrespondingtypesofmatureformedelementsoftheblood,alsocalledperipheral-bloodcells.Aswewillseeinthefollowingchapters,thebonemarrowcanbedividedintotwomajorcellularcompartments:1.Onecomposedwithhematopoieticstemcells(HSCs)whichhavetwomajorphysiologicalproperties:A.Selfrenewalwhichisessentialforthemaintenanceoflife-longhematopoiesis,and:BDifferentiationintocommittedprogenitors.2.Theothercomposedofmultipotentprogenitorcells,whichcannotrenew,butratherdivideanddifferentiateintoallmatureformedelementsoftheblood.Atfirstglance,thefactthatthebonemarrowtissueresidesinthebonecavitiesofallbonedoesnotimplythattheboneitselfhasanyroleintheprocessofhematopoiesis.Asamatteroffact,themechanismsofboneandbloodformationhavetraditionallybeenviewedasdistinctunrelatedprocesses.Compellingevidencenowsuggeststhattheyareintertwined.IthasbeenobservedforalongtimethatHSCsarenotrandomlydistributedinthebonemarrowtissue.Infact,theyresideincloseproximitytoendostealsurfacesofthebone.Itwasthereforehypothesizedthattheosteoblasts,themainboneformingcells,andthereforenotonlytheHSCs,playacentralroleintheprocessofhematopoiesis.ThecloseintimacyoftheHSCandtheboneendostealsurfacesisattheoriginoftheconceptoftheStemCellNichewhichwewilldiscussindetaillateron.ThereforeitseemsthatnormalhematopoiesisreliesonthecomplicityofosteoblastsandHSCs.Thepurposeofthislectureistoreviewindetailthebasicphysiologicalaspectsofhematopoiesis,anddiscussbrieflysomebonemarrowfailuremechanisms.OntogenyofHematopoiesisHematopoiesisbeginsinbloodislandslocatedinextraembryonictissues(fetalyolksac)inthefirsttrimesterandintheaorto-gonad-mesnenophros(AGM)region.Atapproximately6weeksofgestation,hematopoiesisoccurspredominantlyinthefetalliver.Beginningatmidterm,themedullarycavitygraduallyreplacesthefetalliverasthemainsiteofhematopoiesis.Insomespecies,suchasthemouse,thespleenisamajorsiteofhematopoiesisintheadult.Theyolksacismembranoussacattachedtoanembryo,providingearlynourishmentintheformofyolkinprimitivemammalsandfunctioningasthecirculatorysystemofthehumanembryobeforeinternalcirculationbegins.Theprimitiveyolksacparticipatesinnutrientexchangebetweenthefetalandmaternalcirculationsbeforetheformationoftheplacenta.Figure1:PrimitiveyolksacTheyolksacisanextraembryonicstructureresponsiblefortheinitialandtransientproductionofredcellsintheembryo,mainlyduringthefirsttwoweeksofgestation.Beforeplacentalcirculationisestablished,theyolksacconstitutestheprimarysourceofexchangebetweenthemotherandtheembryo(between7-11weeks=7mmindiameter)andconstitutestheveryfirstsiteofhematopoiesis.Thefirstbloodcellsobservedintheembryoarelargenucleatederythroblastsgeneratedinbloodislandsoftheextraembryonicyolksac.These

uniqueredcellshavebeentermedprimitivebecauseoftheirresemblancetonucleatederythroblastsofnon-mammalianspecies.Itisnowwidelyassumedthathematopoiesisintheyolksacisprimitiveandthatdefinitivehematopoiesishasitsoriginsintheaorta/gonad/mesonephros(AGM)region.Thefirstmaturingbloodcellsandcommittedprogenitorsareprovidedbytheyolksac,allowingsurvivaluntilAGM-derivedhematopoieticstemcellscanemerge,seedtheliveranddifferentiateintomaturebloodcells.Stem-cellactivityinthehumanyolksachasnotbeenreported.TheAGMisaregionofembryonicmesodermthatdevelopsduringembryonicdevelopmentandisthesiteoforiginofthedefinitiveHSC.Ithasanintraembryoniclocation(asopposedtoextraembryonicfortheyolksac)andisthesiteofresidenceandamplificationofthedefinitivehematopoieticstemcellsthateventuallyseedthefetalliverandadultbonemarrow(seefigure2).Figure2:TheembryonicAorto-Gonad-Mesonephros(AGM)regionFigure2:TheembryonicAorto-Gonad-Mesonephros(AGM)regionInitiationofhematopoieticstemcells(HSC)intheaorta-gonad-mesonephros(AGM)regionin10-dayembryosisobservedwithadditionalexpansionandmigrationtothefetalliver(FL).Intheadultmouse,boththespleen(SP)andbonemarrow(BM)havehematopoieticactivity.Atapproximately6weeksofgestation,hematopoiesisoccurspredominantlyinthefetalliver.Yolksachematopoieticcellsarelargelyatransientembryonicpopulationandthedefinitivestemcell,infact,derivesfromAGMregion.Beginningatmidterm,themedullarycavitygraduallyreplacesthefetalliverasthemainsiteofhematopoiesis.FETUSwSBodolEEoHMonthsSkeletonDistalLongBones

FETUSwSBodolEEoHMonthsSkeletonDistalLongBonesFigure3:SummaryoftheontogenyofhematopoiesisFigure3showsthechronologicaldescriptionandrespectivesitesofhematopoiesisduringthedevelopmentofahumanbeing.YolksacAGMLIVER

SPLEENBONE

MARROWFirst2,weeksWeefe3and4Firstto9thYolksacAGMLIVER

SPLEENBONE

MARROWFirst2,weeksWeefe3and4Firstto9thmonth3rdmonthlifeDescriptionoftheHematopoieticStemCell(HSC).Hematopoieticstemcells(HSCs)areasubsetofbonemarrowcellsthatarecapableofself-renewalandofterminaldifferentiationintoalltypesofmatureformedelementsoftheblood(seefigure4).TheHSC“niche”,theinvivoregulatorymicroenvironmentwhereHSCsreside,andthemechanismsinvolvedincontrollingthenumberofadultHSCswillbediscussedlaterEachdayanadultproducesapproximately200billionerythrocytes,100billionleukocytes,and100billionplatelets.Moreover,theseratescanincreasebyafactoror10ormorewhenthedemandforbloodcellsincreases.AllthisproductionreliesonthepresenceofanadequatenumberofHSCs.Inthehaematopoieticsystem,HSCsareheterogeneouswithrespecttotheirabilitytoself-renew.Multipotentprogenitorsconstitute0.05%ofbone-marrowcells,andcanbedividedintothreedifferentpopulations:long-termself-renewingHSCs(LT-HSC)short-termself-renewingHSCs(ST-HSC)andmultipotentprogenitors(MPP)withoutdetectableself-renewalpotential(seefigure4).Thesepopulationsformalineageinwhichthelong-termHSCsgiverisetoshort-termHSCs,whichinturngiverisetomultipotentprogenitors.AsHSCsmaturefromthelong-termself-renewingpooltomultipotentprogenitors,theyprogressivelylosetheirpotentialtoself-renewbutbecomemoremitoticallyactive.Whereaslong-termHSCsgiverisetomaturehematopoieticcellsforthelifetimeofthemouse,short-termHSCsandmultipotentprogenitorsreconstitutelethallyirradiatedmiceforlessthaneightweeks.

LT^HSCStMcmST-HSCpragenJorCtimmincdFigure4DescriptionoftheHSCcompartmentwithLT-HSC,ST-HSCandthemultipotentialprogenitorcompartment(MPP).Blood-celldevelopmentprogressesfromahematopoieticstemcell(HSC),whichcanundergoeitherself-renewalordifferentiationintoST-HSCandthemultipotentialprogenitorcells(MPP).MPPgiverisetotwomajormultilineagecommittedprogenitorcells:acommonlymphoidprogenitor(CLP)oracommonmyeloidprogenitor(CMP).Thesecellsthengiverisetomore-differentiatedprogenitorsultimatelygivingrisetounilineagecommittedprogenitorsforBcellsNKcellsTcellsgranulocytesmonocyteserythrocytesandplatelets.HSCscannotundergonormalsomaticmitoticactivityasanyotherkindofcellsinthebodyasillustratedinfigure5.Symmetricaldivisionduringnormalmitoticactivity.Ifitwould,then,bydefinition,bygivingrisetotwoidenticaldaughtercellstroughsymmetricaldivisionwouldexhausttheHSCpool.Inordertomaintainaconstantthepooloflong-termHSCsanindividualstemcellhastogiverisetotwonon-identicaldaughtercells,onemaintainingstem-cellidentityandtheotherbecomingadifferentiatedcellbydivisionalasymetry.Therearetwomechanismsbywhichthisasymmetrycanbeachieved,dependingonwhetheritoccurspre-(divisionalasymmetry),orpost-(environmentalasymmetry)celldivision.1copyrigl明2 M.iture-Kj'hli同CJrcsupFlatur?Rrvdcrwa|Immu「alagyNatureReviewsIniiniiiiol2006;6:93-106AsymmetricaldivisioninHSCsinthebonemarrowAsshowninfigure6,ina,cell-fatedeterminantsareasymmetricallylocalizedtoonlyoneofthetwodaughtercells,whichretainsstem-cellfate,whiletheseconddaughtercelldifferentiates.Inb,duringenvironmentalasymmetry,afterdivision,oneoftwoidenticaldaughtercellsremainsintheself-renewingnichemicroenvironmentwhiletheotherrelocatesoutsidethenichetoadifferent,differentiation-promotingmicroenvironment.Maintenanceoflong-termHSCsandregulationoftheirself-renewalanddifferentiationisthusmaintainedthroughasymetricaldivision.ThemaincharacteristisofHSCaretheirquiescentstate.Theydivideinfrequentlyandcanbequiescentforweeksorevenmonths.Theyalsoareveryfewinnumbers,representing0.05%ofallbonemarrowcells.Finally,theyaretheonlycellsablesoself-renewforever,forlife-time,andableatthesametimetogivebirthtocellsthatwilldivideandmatureintoformedelementsoftheblood.

ConceptoftheHematopoieticStemCellniche.HSCsresideinthecavityoflongandaxialbones.Aswewillsee,theyaresurroundedbyaspecialmicroenvironmentdefinedasthestroma.Thestromaiscomposedofcellsderivedfrommesenchymalstemcells(MSCs),whichgiverisetoamixtureofcellsincludingfibroblasts,adipocytes,endothelialcellsandosteoblasts.EachofthesestromalcellsisessentialforsupportingtheHSCsintheirphysiologicalrole.Hematopoiesiscannotoccuraloneandneedsallthesecellpartnersformingthemicroenvironmentorniche.ThisiswheretheconceptofaHSCnichecomesintoplay.Aswewillsee,intheniche,theosteoblastsplaythemostimportantroleinsupportinghematopoiesis.Astem-cellnichecanbedefinedasaspatialstructureinwhichHSCsarehousedandmaintainedbyallowingself-renewalintheabsenceofdifferentiation.Thestem-cellnichefunctionsincludestorageofquiescentstemcells,self-renewalandinhibitionofdifferentiation.Themainfunctionofaself-renewingnichewouldbetoguaranteethatbyenvironmentaland/ordivisionalasymmetry,oneofthetwodaughtersofadividingstemcellmaintainsthestem-cellfatewhiletheotherproducesdifferentiatingprogenitors.CenterofbonemarrowIsSiamcallsStemC&lls1998;16:7-15EccfcXlwf-jm± tSisnuiQcyiei.印血,ttyslwdCenterofbonemarrowIsSiamcallsStemC&lls1998;16:7-15EccfcXlwf-jm± tSisnuiQcyiei.印血,ttyslwdprqgDnllrrPlakslelaLwrnphaIdpFowviilnrchIIeBonemarrownicheorganizationshowingthattheHSCsarenotrandomlydistributedinthebonecavitybutratherconcentratedandattachedtotheendostealsurfacesofthebone,morespecificallytoosteoblasts.Themorematureprogenitorcellstendtolocalizeinthemiddleofthecavity.Themechanismsofboneandbloodformationhavetraditionallybeenviewedasdistinct,unrelatedprocesses,butcompellingevidencesuggeststhattheyareintertwined.BasedonobservationsthatHSCsresideclosetoendostealsurfacesofthebonesasshowninfigure7,itwashypothesizedthatosteoblastsplayacentralroleinhematopoiesis.Wewillseethatosteoblastsarecriticalintheregulationofhematopoiesisandareoneofthemostimportantregulatorycellsinthestemcellniche.Toputitverysimply,“noosteoblasts,nohematopoiesis”.Severalanimalmodelsstronglyimplicateosteoblastsinhematopoiesisbyvirtueofcreating

aniche.Inmicewithamaturationalarrestofosteoblasts,thereisatotallackofbonemarrowthroughouttheentireskeletonandthereforetotalabsenceofhematopoiesis.AnatomicaldescriptionoftheHematopoieticStemCellniche.WheredowefindtheHSCsnichesthataresoimportantformaintaininghematopoiesisforlifebyvirtueoftheirprotectiveeffectonLT-HSCs?Ifonelookscarefullyattheanatomicalaspectsbonesingeneral,includinglongbones,thereisaspecialareacalledspongyboneorcancellousbone(seefigure8).Forlongbones,cancellousboneisattheepiphysis.Longeon皆EpiphysisDiSpHy^iSMeflul出時(shí)caMtyNutientraramentndesteumPeriosteumspDftf/tiDneLongeon皆EpiphysisDiSpHy^iSMeflul出時(shí)caMtyNutientraramentndesteumPeriosteumspDftf/tiDne￡pnprys&ailineAlsotermed

canc?llous

boneFigure8Anatomicalschemaofalongbonewithspongyor“cancellousbone”attheepiphysisthisistheanatomicalareawheremostLT-HSCsresideincontactwithosteoblastsinaclosenetworkoftrabecula(seetext).Thistypeofbone(spongyorcancellous)ismostlyfoundintheaxialskeleton.Asshowninfigure3,theaxialskeletonisthemajorsiteofhematopoiesisintheadult.Cancellousboneisaspongytypeofbonewithaveryhighsurfacearea,foundattheendsoflongbonesandaxialbones(vertebrae).Theveryhighsurfaceareaistheresultofacomplexnetworkoftrabecula,whicharefinebonespicules.Thespiculesformalatticework,withintersticesfilledwithbonemarrowwhereLT-HSCareinintimatecontactwithosteoblastsandothermesenchymalcellssuchasadipocytes,endothelialcellsandfibroblasts(seefigure9).CancellousBoneTrabeculaeDiooavessels uanaiicuiusFigure9AnatomyoftheHSCnicheinthecancellousorspongybonewiththepresenceofanetworkoftrabeculaecreatingmultiplespacestherebyincreasingthesurfaceareawhereHSCscancomeinintimatecontactwithosteoblastsandprovidelife-longhematopoiesisIntheHSCniche,althoughthesurvivalofHSCsrequiresintimatecell-cellcontactwithosteoblasts,onemustrememberthatbonemarrowstromalcellsderivedfrommesenchymalstemcells,includingfibroblasts,adipocytesandendothelialcellsarealsoimportantinsupportingHSCsbysecretionofimportantsurvivalproteins.Insummary,themainanatomicalsiteoftheHSCnicheisinthespongyorcancellousbonewhereonefindsasignificantincreaseinbonesurfaceareaensuringandincreaseandadequatenumberofLT-HSCs.Aswewillsee,thecontroloftheHSCnumbersisdirectlyrelatedtothenumberofosteoblasts.Byincreasingthebonesurfacearea(bythesametokenthenumberofosteoblasts)throughthenetworkofbonetrabecula,thereisaparallelincreaseinthenumberofLT-HSCs.Intheadult,thespongyorcancellousboneisfoundmainlyattheproximalendsofthehumerusandfemur,inthevertebrae,ribs,sternumandpelvis.FunctionaldescriptionoftheHematopoieticStemCellniche.ThefunctionsofthenicheincludeadhesiveinteractionbetweenHSCsandtheniche.Although,asstatedearlier,fourdifferentstromalcellsinterplaywithinthatniche,suchasadipocytes,endothelialcells,fibroblastsandosteoblasts,themajorfunctionoftheHSCnicheistoregulatethenumberofHSCsthroughacomplexinteractionwithosteoblasts.ThisiswhyHSCslocalizeclosetotheendostealliningofbone-marrowcavitiesintrabecularregionsoflongbones,whereasmoredifferentiatedhematopoieticprogenitorsarefoundmainlyinthecentralbone-marrowregion(seefigure7).QuiescentHSCsdetachfromtheendostealnicheandmigratetowardsthecentreofthebonemarrowtothevascularzonefromwheretheyestablishhematopoiesis.Thisspecificsite(centerofthebonemarrow)ismostlypopulatedwithendothelialcells,fibroblastsandadipocytes.Itiscalledthevascularniche,asopposedtotheendostealniche.Collectively,thevascularandendostealnichesstronglycooperatetocontrolHSCquiescenceandself-renewingactivity(andthereforeHSCnumbers),aswellastheproductionofearlyprogenitorstomaintainhomeostasisorre-establishitafterinjury.ThemainfunctionsHSCsnichesaretostoreHSCs,ensuretheirselfrenewalandinhibittheirdifferentiation.Asstatedearlier,HSCsareinintimatecontactwithbone(osteoblasts),andcell-cellcontactisresponsiblefortheapparentlyunlimitedproliferativecapacityandinhibitionofmaturationofHSCs.Micewithdefectsinosteoblastdifferentiationandconsequentfailuretoformbonehavedefectivebonemarrowhematopoiesis.AnincreaseinthenumberofosteoblastsdirectlycorrelateswiththenumberoffunctionalLTHSCs,indicatingthatosteoblastsareanessentialpartoftheendostealnicheandarelimitingfornichesizeand/oractivity.Nature2003;425:041-45Figure10Epiphysisofanormalmouse(WT)andamousethathasbeenengineered(Tg)toproducemorebone.Thereisasignificantincreaseinthenetworkoftrabeculae(bonespicules)intheengineeredmousecorrelatingwithanincreaseintheLT-HSCsnumbers.Insummary,themainfunctionoftheendostealnichewheremostfibroblastsarefoundistoprotectLT-HSCs,maintainacriticalnumberbyinhibitingapoptosisandunnecessarydifferentiationtowardmorematureprogenitors.AbsenceofthiscrucialfunctionwouldleadtoadepletionoftheLT-HSCpoolandbonemarrowfailure.Themainfunctionofthevascularnicheistosupportandpromotethedifferentiationandmaturationofmorematureprogenitorsintothewellknownformedelementsofthebloodthroughsecretionofdifferentproteins(growthfactors—seenextsection)bystromalcells(seefigures11and12).FigureFigure#Erythropoietinisthefavoritedrugofthebikersfromthe“TourtheFrance”.Nowonder,EPOinducesterminalerythrocytedevelopmentandregulatesRBCproductionandthereforetissueoxygenation..Thejuxtatubularinterstitialcellsoftherenalcortex,whichproduceapproximately90percentoftheerythropoietininbloodsenseoxygenlevelsandtriggerserythropoietinformation.Erythropoietinpromotestheproliferationoferythroidprogenitorcellsbyreducingthelevelofcell-cycleinhibitorsandsupportstheirsurvivalbyincreasinganantiantiapoptosisprotein.Eliminationoftheerythropoietingeneoritsreceptorinmicecausessevereanemiaanddeath.Theadministrationoferythropoietintoanimalsorhumansincreasesthenumberoferythroidprogenitorcells,whichdifferentiateintonormoblasts,enucleate,andleavethebonemarrow.Granulocytecolony-stimulatingfactor(G-CSF)G-CSFisaglycoproteinproducedbyanumberofdifferenttissuestostimulateacommittedprogenitortoproducematureneutrophils.Italsostimulatesthesurvival,proliferation,differentiation,andfunctionofneutrophilgranulocyteprogenitorcellsandmatureneutrophils.AsopposedtoIL-3whichaffectsaprogenitorcellthatismultipotential,G-CSFtriggersthedifferentiationofaprogenitorcellonlycommittedtoneutrophilicdifferentiationandmaturation.InoncologyarecombinantformofG-CSFisusedtoacceleraterecoveryfromneutropenia.Chemotherapycancausemyelosuppressionandunacceptablylowlevelsofneutrophils,subjectingpatientstoinfectionsandsepsis.Thrombopoietin(TPO)Thrombopoietinistheprimaryregulatorofplateletproduction.Itsupportsthesurvivalandproliferationofmegakaryocyteprogenitors.Invitro,thrombopoietininducesthedifferentiationofprogenitorcellsintolargemegakaryocytes,eachonecapableofproducingthousandsofplatelets.Thrombopoietin,apotentstimulatorofplateletproduction,causesthrombocytosiswhenadministeredtoanimalsorhumans.Inmice,eliminationofthethrombopoietingeneoritsreceptorreducesthelevelofproductionofmegakaryocytesandplateletstoapproximately10percentofnormal.8.Theformationofmaturebloodelements:1.MyelopoisisBydefinition,myelopoisisistheprocessthatgivesrisetoformedelementsofthebloodincludingredcells(erythropoiesis),platelets(thrombopoiesis)andgranulocytes(granulopoiesis).TheseformedelementsofthebloodaretheproductsoftheCommonMyeloidProgenitor(CMP)(seefigure14).ErythropoiesisMaturationalanddifferentiationsequencefromtheimmatureproerythroblaststomatureenucleatedredcells.ThematurationsequenceoftheprogenycomingfromCFU-Eistheproerythroblasts,tobasophilicerythroblast,topolychromaticerythroblast,toorthochromaticerythroblasttoerythrocyte.Figure16Abonemarrowsmearshowingthematurationsequencefromtheproerythroblasts(1),tobasophilicerythroblast(2)topolychromaticerythroblast,toorthochromaticerythroblast(3)toerythrocyte.Asshowninfigure14,erythropoiesisisinitiatedbyprogenitorswithahighproliferationratecalledBurstFormingUnitsErythroid(BFU-E)andfollowedbyasecondtypeofprogenitors,ColonyFormingUnitsErythroid(CFU-E).ThefirstidentifiablecellinabonemarrowsmearfrommaturationofCFU-Eistheproerythroblast,showninfigure16(1).GranulopoiesisForthesakeofsimplicity,Iwillbrieflydescribethegranulocytematurationandmakenomentionaboutthemonocytelineage.Granulopoiesisisthedevelopmentofthegranulocyticwhitebloodcells,theneutrophils,thebasophilsandtheeosinophils.Figure17showstheexampleofneutrophilicdifferentiationandmaturation.Thefirstidentifiableprecursorofthegranulocytesinabonemarrowunderthemicroscopeisthemyeloblast.Asshowninfigure14,theColonyFormingUnit-Granulocyte(CFU-G),undertheinfluenceofGCS-F,maturesintosixdistinctmorphologicalstages:Myeloblast,Promyelocyte,Myelocyte,Metamyelocyte,Band,and,Segmentedneutrophil(figure18).Theneutrophilisthechiefphagocyticleukocyteofthebody.Ithasahalflifeofonly6hoursinthebloodanditsmainroleistomigratetositesofinfection.

WBC-GRANULOCYTOPOItSISFigure17Adescriptionofthedifferentstagesofmaturationoftheneutrophiliclineage.After5to6daysofmaturationanddifferentiationinthebonemarrow,theneutrophilstaysonly6hoursinthecirculationandthenmigratestotissues.Figure18Morphologicalcharacteristicsofthedifferentstagesofmaturationoftheneutrophiliclineageastheyappearunderthemicroscopeonabonemarrowsmear:Upperlefttoright,theMyeloblast,PromyelocyteandMyelocyte.Lowerrighttoleft:theMetamyelocyte,BandandMatureNeutrophil..Thrombopoiesis.Thrombopoiesisistheprocessofformationofplateletsfromimmatureprecursors.Thenormalsequenceofmaturationisfromtheearlymegakaryoblast(1),tothemegakaryoblast(2),themekagaryocyte(3)andfinallymatureplatelets(4)detachingfromthecytoplasmofmegakaryocytes.ThegenerationtimefromtheLT-HSCtomatureplateletproductionisabout10days.Asshowninfigure14,theColonyFormingUnitMegakaryocyte(CFU-Meg)givesrisetotheearliestidentifiablecellofthislineagewhichistheearlymegakaryoblast(no#1infigure19).Figure19IdentifiableprogenyoftheCFU-Meginthebonemarrow:Earlymegakaryo