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Lecture1Hematopoiesis1.Introduction2.Ontogenyofhematopoiesis3.DescriptionoftheHematopoieticStemCell(HSC)4.Theconceptofthestemcellniche5.Anatomicaldescriptionofthestemcellniche6.Functionaldescriptionofthestemcellniche7.Roleoflineage-specificGrowthFactorsinhematopoiesis8.Theformationofmaturebloodelements:1.Myelopoiesis1.Erythrocytes2.Granulocytes3.Platelets9.Theformationofmaturebloodelements:2.Lymphopoiesis1.Tcells2.Bcells3.NKcells10.BoneMarrowFailure1.Inheriteddisorders2.Acquireddisorders1.IntroductionTheformedelementsoftheblood,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.2.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.Theseuniqueredcellshavebeentermedprimitivebecauseoftheirresemblancetonucleatederythroblastsofnon-mammalianspecies.Itisnowwidelyassumedthathematopoiesisintheyolksacisprimitiveandthatdefinitivehematopoiesishasitsoriginsintheaorta/gonad/mesonephros(AGM)region.Thefirstmaturingbloodcellsandcommittedprogenitorsareprovidedbytheyolksac,allowingsurvivaluntilAGM-derivedhematopoieticstemcellscanemerge,seedtheliveranddifferentiateintomaturebloodcells.Stem-cellactivityinthehumanyolksachasnotbeenreported.TheAGMisaregionofembryonicmesodermthatdevelopsduringembryonicdevelopmentandisthesiteoforiginofthedefinitiveHSC.Ithasanintraembryoniclocation(asopposedtoextraembryonicfortheyolksac)andisthesiteofresidenceandamplificationofthedefinitivehematopoieticstemcellsthateventuallyseedthefetalliverandadultbonemarrow(seefigure2).Figure2:TheembryonicAorto-Gonad-Mesonephros(AGM)regionInitiationofhematopoieticstemcells(HSC)intheaorta-gonad-mesonephros(AGM)regionin10-dayembryosisobservedwithadditionalexpansionandmigrationtothefetalliver(FL).Intheadultmouse,boththespleen(SP)andbonemarrow(BM)havehematopoieticactivity.Atapproximately6weeksofgestation,hematopoiesisoccurspredominantlyinthefetalliver.Yolksachematopoieticcellsarelargelyatransientembryonicpopulationandthedefinitivestemcell,infact,derivesfromA