01. Hematopoiesis

Hematology lectures

1. Hematopoiesis
(Basic Concepts)
Lecture (1)

2. LectureObjectives:
•Definitionofhematopoiesis.
•Anatomyofhematopoiesis.
•Thecellularpathwaysofhematopoiesis.
•Specificdifferentiationpathways.
•Hematopoieticgrowthfactors.
•Theformationofbloodcells.

3. DefinitionofHematopoiesis:
•Productionofredbloodcells,whitecells,
andplatelets(bloodcellformation).

4. AnatomyofHematopoiesis:
•FirstTrimester:YolkSac
•SecondTrimester:LiverandSpleen
•ThirdTrimester:Central,PeripheralSkeleton
•Adulthood:AxialSkeleton
oVertebralBodies
oSternum
oRibs
oPelvis
•Hematopoiesismayre-expandintofetalsitesintimesofseveredemand,
e.g.thalassemia,MF(Extramedullaryhematopoiesis).

5. •OverallCellularOrganizationofHematopoiesis:
1.StemCells:
ØTotipotential.
ØMultipotential.
2.ProgenitorCells.
3.PrecursorCells.
4.EffectorCells.
The cellular pathways of hematopoiesis:

6. I. Stem cells:
TotipotentialStem Cells :"The Godfather Cells”:
1.UnlimitedSelf-Renewal.
2.UnlimitedDifferentiation:cangiverisetoanycellularelement.
3.PresentinMarrowinSmallNumbers.
4.HighlyResistanttoChemotherapy.
5.ResidePrimarilyinMarrow.Smallnumberscirculateinblood.
6.SurfaceAntigen-CD34+("ClusterofDifferentiation34").
7.LooklikeSmallLymphocytes.
8.Dysfunctionleadstoaplasticanemiaorcertaintypesofleukemia.
The cellular pathways of hematopoiesis:

7. MultipotentialStemCells:-i.e.Lymphoid,MyeloidStemCells
1.DerivedfromTotipotentialStemCells.
2.CapableofExtendedSelfRenewal.
3.CapableofExtendedDifferentiation
•Lymphoidstemcellsgiverisetoallcategoriesofmaturelymphocytes.
•Myeloidstemcellsgiverisetoredcells,granulocytes,monocytes,and
platelets.
4.Lymphoidstemcellcangiverisetoso-called"lymphoproliferative"
malignanciessuchasacutelymphocyticleukemia
5.MyeloidStemcellcangiverisetoso-called"myeloproliferative”
malignanciessuchasacutemyeloidleukemia
The cellular pathways of hematopoiesis:

8. II.ProgenitorCells-CFU's(ColonyFormingUnits):
1.DerivedfromMultipotentialStemCells.
2.Capableoflimitedself-renewal.
3.Capableoflimiteddifferentiation.
•CFU-GEMM(colonyformingunit-granulocyte,erythrocyte,macrophage,
megakaryocyte).
•CFU-ME(colonyformingunit–megakaryocyte-erythrocyte).
•CFU-GM(colonyformingunit–granulocyte-monocyte).
•CFU-G(colonyformingunit-granulocyte).
4.ResponsivetoHematopoieticGrowthFactors,e.g.ErythropoietinstimulatesCFU-E,
GM-CSFstimulatesCFU-GM,G-CSFstimulatesCFU-G,etc.
5.Expressdifferentiationantigens-surfaceproteinssuchasCD19-B-lymphocyte.
The cellular pathways of hematopoiesis:

9. III.PrecursorCells-Blastsandtheirprogeny:
•Firstmorphologicallyidentifiablecells:
oErythroblast-RedCells.
oMyeloblast-Granulocytes.
oMonoblast–Monocytes.
oLymphoblast–Lymphocytes.
oMegakaryoblast–Platelets.
•Littleifanyself-renewal.
The cellular pathways of hematopoiesis:

10. IV.MatureEffectorCells:
•RedCells:carryoxygen,carbondioxide;lifespan120
days.
•Neutrophils:phagocytosis,killing.
•Monocytes:phagocytosis,killing,antigenpresentation.
•Lymphocytes:identifycellsasselfornon-self.
•Platelets:hemostasis.
The cellular pathways of hematopoiesis:

12. Specific differentiation pathways:
I.Neutrophils-Granulopoiesis:
1.TotipotentStemCell-CD34+
2.MyeloidStemCell
3.Progenitor-CFU-GM
4.Progenitor-CFU-G
5.Precursors
•Myeloblast
•Promyelocyte
•Myelocyte
•Metamyelocyte(Juvenile)
•Band(Staff)
•Neutrophil
•KineticsofNeutrophilProduction-14daysfrom
myeloblasttoneutrophilcorrespondstotimefor
neutrophilrecoveryfollowingchemotherapy

13. II.RedCells–Erythropoiesis:
1.TotipotentStemCell-CD34+
2.MyeloidStemCell
3.Progenitor-BFU-ME
4.Progenitor-CFU-ME
5.Precursors
•Proerythroblast
•Basophilicerythroblast(Early)
•Polychromatophilicerythroblast(Intermediate)
•Orthochromaticerythroblast(Late)
•Reticulocyte
•Erythrocyte
•Kineticsofredcellproduction:5daysfrom
erythroblasttoreticulocytecorrespondstotimeto
responsetoirontherapyinirondeficiency.
Specific differentiation pathways:

14. III.Lymphocytes–Lymphopoiesis:
1.AntigenIndependentPhase:
•Initiallymphopoiesistakesplaceinbonemarrow.
•Maturationtakesplacesinlymphnodes,thymus.
2.AntigenDependentPhase:
•Secondcycleofdifferentiationandproliferationin
responsetoantigenexposure.
3.MemoryPhase:
•Followsantigenexposure
•Mayliveforyears
Specific differentiation pathways:

15. IV. Platelets –Megakaryopoiesis:
1.Promegakaryoblast(MK-1)
2.Megakaryoblast(MK-2) -DNA replication
without cell division
3.Megakaryocyte (MK-3) -polyploidnucleus
4.Platelet release via cytoplasmic fragmentation
Specific differentiation pathways:

16. 1.Erythropoietin(EPO):
•SynthesizedinKidney.
•InducesproliferationofCFU-E.
•Synthesisriseswhenredcelllevelfalls.
2.StemCellFactor(SCF):
•StimulatesTotipotent,PluripotentStemCellstoenter
differentiationpathway.
Hematopoietic Growth Factors:

17. 3.Granulocyte-MonocyteColonyStimulatingFactor(GM-CSF):
•Secretedbylymphocytes,endothelialcells,stromalcellsinmarrow.
•Stimulatesproductionofgranulocytes,monocytes.
•Commerciallyavailable.
4.GranulocyteColonyStimulatingFactor(G-CSF):
•Secretedmainlybymarrowstromalcells.
•Mainly,butnotexclusively,stimulatesproductionandfunctionofgranulocytes.
•Synthesisrisesinresponsetoinfections.
Hematopoietic Growth Factors:

18. 5.Interleukins(IL1,IL2,IL3,...IL13):
•Mediatemultiple,highlycomplexcommunications
betweenvariousclassesofwhitebloodcells.
•Levelsriseinresponsetoinfections.
Hematopoietic Growth Factors:

19. •Allthevarioustypesofbloodcellsareproducedinthebonemarrowarise
fromasingletypeofcellcalledapluripotentstemcell.
•Thesestemcells:
oareveryrare(onlyaboutonein10,00bonemarrowcells);
oareattached(probablybyadherensjunctions)toosteoblastsliningthe
innersurfaceofbonecavities;
oexpressasurfaceproteindesignatedCD34;
oproduce,bymitosis,twokindsofprogeny:
Ømorestemcells.
ØCellsthatbegintodifferentiatealongthepathsleadingtothe
variouskindsofbloodcells.
The formation of blood cells:

20. Whichpathistakenisregulatedbytheneedformoreofthattypeofbloodcell
whichis,inturn,controlledbyappropriatecytokinesand/orhormones.For
example:
•Interleukin-7(IL-7)isthemajorcytokineinstimulatingbonemarrowstemcells
tostartdownthepathleadingtothevariouslymphocytes(mostlyBcellsandT
cells).
•Erythropoietin(EPO),producedbythekidneys,enhancestheproductionof
redbloodcells(RBCs).
•Thrombopoietin(TPO),assistedbyInterleukin-11(IL-11),stimulatesthe
productionofmegakaryocytes.Theirfragmentationproducesplatelets.
•Granulocyte-monocytecolony-stimulatingfactor(GM-CSF),asitsname
suggests,sendscellsdownthepathleadingtoboththosecelltypes.Indue
course,onepathortheotheristaken.

21. •Undertheinfluenceofgranulocytecolony-stimulatingfactor(G-
CSF),theydifferentiateintoneutrophils.
•Furtherstimulatedbyinterleukin-5(IL-5)theydevelopinto
eosinophils.
•Interleukin-3(IL-3)participatesinthedifferentiationofmostofthe
whitebloodcellsbutplaysaparticularlyprominentroleinthe
formationofbasophils(responsibleforsomeallergies).
•Stimulatedbymacrophagecolony-stimulatingfactor(M-CSF)the
granulocyte/macrophageprogenitorcellsdifferentiateinto
monocytes,theprecursorsofmacrophages.