HEMATOPOIESISHEMATOPOIESIS
A lecture by: A lecture by:
Maximo B. Axibal, Jr. Maximo B. Axibal, Jr.
MD FPSPMD FPSP
HEMATOPOIESISHEMATOPOIESIS
DEF: Process of ____ of cellular DEF: Process of ____ of cellular elements of the bloodelements of the blood Production,Production, Differentiation,Differentiation, Maturation &Maturation & Proliferation Proliferation
Stages: Fetal or adult?Stages: Fetal or adult?
HEMATOPOIESIS HEMATOPOIESIS Types of MaturationTypes of Maturation
SynchronousSynchronous AsynchronousAsynchronous
MedullaryMedullary ExtramedullaryExtramedullary
IntroductionIntroduction
BM largest tissue in the bodyBM largest tissue in the body Adult: 4 L; Child: 1. 6 LAdult: 4 L; Child: 1. 6 L BM 1° site for blood cell formationBM 1° site for blood cell formation
2.5 billion RBCs / kg / day 2.5 billion RBCs / kg / day 2.5 billion platelets / kg / day2.5 billion platelets / kg / day 1 billion granulocytes / kg / day 1 billion granulocytes / kg / day
IntroductionIntroduction
# of circulating blood cells depends # of circulating blood cells depends on:on: Rate of productionRate of production Rate of releaseRate of release SurvivalSurvival
Production & destruction occur Production & destruction occur simultaneously & constantlysimultaneously & constantly
INTERRELATIONSHIP INTERRELATIONSHIP OF BLOOD CELLS: OF BLOOD CELLS:
TheoriesTheories Monopheletic (Downey, Ferat & Monopheletic (Downey, Ferat &
Pappenheim)Pappenheim) Polypheletic (Piney, Naegali, Polypheletic (Piney, Naegali,
Schilling, Rosenthal, Osgood, Sabin, Schilling, Rosenthal, Osgood, Sabin, Cunningham & Doan)Cunningham & Doan)
NaegaliNaegali Modification of SchillingModification of Schilling Sabin & her co-workersSabin & her co-workers
HEMATOPOIESISHEMATOPOIESIS
HEMATOPOIESIS: HEMATOPOIESIS: Mesenchymal periodMesenchymal period
Start: 4th wk AOGStart: 4th wk AOG End: 2nd mon AOGEnd: 2nd mon AOG
Products: Products: Nucleated megaloblastic RBC's (2 Nucleated megaloblastic RBC's (2
wks AOG)wks AOG) Minor production of MKsMinor production of MKs
HEMATOPOIESIS: HEMATOPOIESIS: Mesenchymal (Yolk Sac) Mesenchymal (Yolk Sac)
periodperiod Mesoblastic(19-20 Mesoblastic(19-20
d):d):
Erythropoietic Erythropoietic IslandsIslands
PNRBCsPNRBCs
Mesodermal (8-12 Mesodermal (8-12 w):w):
ExtraembryonicExtraembryonic 3 Embryonic Hgbs3 Embryonic Hgbs MegakaryopoiesisMegakaryopoiesis
HEMATOPOIESIS: HEMATOPOIESIS: Hepatic period Hepatic period
Start: End of 11th wk AOGStart: End of 11th wk AOG
End: 6th mon AOGEnd: 6th mon AOG
Products:Products: Extravascular erythroblasts & anucleated Extravascular erythroblasts & anucleated
macrocytic RBC'smacrocytic RBC's Megakaryocytes- Megakaryocytes- 6th wk AOG 6th wk AOG Granulocytes- Granulocytes- 6th wk AOG6th wk AOG Lymphocytes- Lymphocytes- 4th mon AOG4th mon AOG Monocytes- Monocytes- 5th mon AOG5th mon AOG
HEMATOPOIESIS: HEMATOPOIESIS: Medullary periodMedullary period
Start: 10th wk AOG (6th mon AOG- Start: 10th wk AOG (6th mon AOG- predominant)predominant)
End: LifetimeEnd: Lifetime
Products:Products: RBC's- 10th wk AOGRBC's- 10th wk AOG ThrombocytesThrombocytes Granulocytes/ monocytesGranulocytes/ monocytes Lymphocytes- w/ contributions from Lymphocytes- w/ contributions from
thymus, L.N. & spleen (Ag independent)thymus, L.N. & spleen (Ag independent)
HEMATOPOIESIS: HEMATOPOIESIS: Medullary periodMedullary period
RBC - Alpha 1 & alpha2 beta2RBC - Alpha 1 & alpha2 beta2 3 wks postpartum – BM (Medullary)3 wks postpartum – BM (Medullary) 4th y - rate of BM production 4th y - rate of BM production
exceeds need for blood cellsexceeds need for blood cells
MATURATION MATURATION FEATURES: NUCLEUS FEATURES: NUCLEUS
(DNA)(DNA) DEC N:CDEC N:C CHROMATIN: CHROMATIN:
HETEROGENOUSHETEROGENOUS HOMOGENOUS HOMOGENOUS (WBC) to (WBC) to CLUMPED (RBC) CLUMPED (RBC)
NUCLEOLI (RNA): NUCLEOLI (RNA): PRESENTPRESENT DISAPPEARSDISAPPEARS
INDENTATION INDENTATION APPEARS APPEARS (GRANULOCYTES)(GRANULOCYTES)
LOBULATIONS LOBULATIONS APPEAR APPEAR (GRANULOCYTES)(GRANULOCYTES)
SOMETIMES SOMETIMES DISAPPEAR (RBC)DISAPPEAR (RBC)
MATURATION MATURATION FEATURES:FEATURES:
CYTOPLASM (RNA)CYTOPLASM (RNA) DEC N:CDEC N:C DEEP BLUEDEEP BLUE LIGHT BLUE (WBC) LIGHT BLUE (WBC)
sometimes PINK (RBC)sometimes PINK (RBC) GRANULES APPEARGRANULES APPEAR CELL SIZECELL SIZE DECREASES IN SIZEDECREASES IN SIZE
Bone Marrow Bone Marrow MorphologyMorphology
(Erythropoiesis)(Erythropoiesis)
HEMATOPOIESISHEMATOPOIESIS
Hematopoietic Regulatory Hematopoietic Regulatory FactorsFactors
Cytokines: Cytokines: Regulate proliferation, Regulate proliferation,
differentiation, differentiation, functionfunction
GlycoproteinsGlycoproteins Multilineage or Multilineage or
lineage specificlineage specific Redundant & complex Redundant & complex
specificitiesspecificities Both positive & Both positive &
negative feedback negative feedback mechanismmechanism
Colony Stimulating Colony Stimulating factors (CSF)factors (CSF)
Interleukins (IL)Interleukins (IL) Stem Cell Factor Stem Cell Factor
(SCF) (SCF) Tumor Necrosis Tumor Necrosis
Factor (TNF)Factor (TNF) Transforming Transforming
growth factors growth factors (TGF)(TGF)
Interferon (IF)Interferon (IF)
GF (1o TARGET)GF (1o TARGET)CHR (SOURCE)CHR (SOURCE)
IL 1 (STEM CELLS, LYMPHOCYTES, IL 1 (STEM CELLS, LYMPHOCYTES, ENDOTHELIAL CELL)ENDOTHELIAL CELL) 2 (MONOCYTE)2 (MONOCYTE)
IL 3 (STEM CELLS, MYELOID, IL 3 (STEM CELLS, MYELOID, ERYTHROID, MK)ERYTHROID, MK) 5 (T CELL)5 (T CELL)
GF (1o TARGET)GF (1o TARGET)CHR (SOURCE)CHR (SOURCE)
IL 4 (BASOPHIL, B/ T LYMPHOCYTE)IL 4 (BASOPHIL, B/ T LYMPHOCYTE) 5 (T CELL)5 (T CELL)
IL 5 (EOSINOPHIL, B LYMPHOCYTE)IL 5 (EOSINOPHIL, B LYMPHOCYTE) 5 (T CELL)5 (T CELL)
IL 6 (STEM CELLS, B/T IL 6 (STEM CELLS, B/T LYMPHOCYTE)LYMPHOCYTE) 7 (WBC, FIBROBLAST)7 (WBC, FIBROBLAST)
GF (1o TARGET)GF (1o TARGET)CHR (SOURCE)CHR (SOURCE)
IL 7 (LYMPHOCYTE)IL 7 (LYMPHOCYTE) ? (WBC)? (WBC)
IL 8 (GRANULOCYTE)IL 8 (GRANULOCYTE) ? (WBC)? (WBC)
IL 9 (GRANULOCYTE)IL 9 (GRANULOCYTE) ? (LYMPHOCYTE)? (LYMPHOCYTE)
G- CSF (ERYTHROID CELLS, MK)G- CSF (ERYTHROID CELLS, MK) 17 (MONO, EC, FIBROBLAST)17 (MONO, EC, FIBROBLAST)
GF (1o TARGET)GF (1o TARGET)CHR (SOURCE)CHR (SOURCE)
M- CSF (MONOCYTE)M- CSF (MONOCYTE) 5 (MONO, EC)5 (MONO, EC)
GM- CSF (GRANULOCYTE, GM- CSF (GRANULOCYTE, MONOCYTE, MK)MONOCYTE, MK) 5 (T CELL, MONO, EC)5 (T CELL, MONO, EC)
EPO (RBCs)EPO (RBCs) 7 (KIDNEY, LIVER)7 (KIDNEY, LIVER)
Hematopoietic Cell Hematopoietic Cell Release Release
Cellular migration:Cellular migration: CordsCords through endothelial cells through endothelial cells circulationcirculation
Normally only mature cells releasedNormally only mature cells released
Immature cells released under abnormal Immature cells released under abnormal circumstances:circumstances:
Immature RBCs- hypoxia, hemolytic anemiasImmature RBCs- hypoxia, hemolytic anemias Immature granulocytes- severe infections, Immature granulocytes- severe infections,
sepsissepsis Marrow replacement- fibrosis, neoplasmMarrow replacement- fibrosis, neoplasm
LYMPHOPOIESISLYMPHOPOIESIS
LYMPHOBLASTLYMPHOBLAST PROLYMPHOCYTEPROLYMPHOCYTE MATURE MATURE
LYMPHOCYTELYMPHOCYTE
LymphopoiesisLymphopoiesis BM & lymphatic organs:BM & lymphatic organs:
T-cellsT-cellsBMBM Thymus Thymus Mature T-cells Mature T-cells PB PB
B cellsB cellsBMBM LN (“educated”) LN (“educated”) PB PB
gut lymphoid tissue, spleen gut lymphoid tissue, spleen
Plasma CellsPlasma Cells
LymphopoiesisLymphopoiesis(Lymphoblasts)(Lymphoblasts)
THROMBOPOIESISTHROMBOPOIESIS
MEGAKARYOBLASMEGAKARYOBLASTT
PROMKPROMK MKMK PLATELETPLATELET
MegakaryopoiesisMegakaryopoiesis
MONOPOEISISMONOPOEISIS
MONOBLASTMONOBLAST PROMONOCYTEPROMONOCYTE MONOCYTEMONOCYTE
MonopoiesisMonopoiesis
Monoblast
Mature Monocytes
Promonocyte
GRANULOPOIESISGRANULOPOIESIS
MYELOBLASTMYELOBLAST PROMYELOCYTEPROMYELOCYTE MYELOCYTEMYELOCYTE METAMYELOCYTE METAMYELOCYTE
(JUVENILE)(JUVENILE) STAB (BAND; STAB (BAND;
STAFF)STAFF) MATURE MATURE
NEUTROPHIL (PMN/ NEUTROPHIL (PMN/ SEG); EOSINOPHIL; SEG); EOSINOPHIL; BASOPHILBASOPHIL
GRANULOPOIESISGRANULOPOIESIS
GranulopoiesisGranulopoiesis(Myeloblast)(Myeloblast)
Granulopoiesis Granulopoiesis (Promyelocyte)(Promyelocyte)
GranulopoiesisGranulopoiesis(Myelocyte)(Myelocyte)
GranulopoiesisGranulopoiesis(Metamyelocyte)(Metamyelocyte)
Granulopoiesis Granulopoiesis (Band)(Band)
GranulopoiesisGranulopoiesis(Segmented Neutrophil)(Segmented Neutrophil)
GranulopoiesisGranulopoiesis(Kinetics)(Kinetics)
Stage/s capable of Stage/s capable of mitosis?mitosis?
MYELOBLASTMYELOBLAST PROMYELOCYTEPROMYELOCYTE MYELOCYTEMYELOCYTE METAMYELOCYTE METAMYELOCYTE
(JUVENILE)(JUVENILE) STAB (BAND; STAB (BAND;
STAFF)STAFF) MATURE MATURE
NEUTROPHIL (PMN/ NEUTROPHIL (PMN/ SEG); EOSINOPHIL; SEG); EOSINOPHIL; BASOPHILBASOPHIL
Stage where azurophilic Stage where azurophilic granule formation begin?granule formation begin? MYELOBLASTMYELOBLAST PROMYELOCYTEPROMYELOCYTE MYELOCYTEMYELOCYTE METAMYELOCYTE METAMYELOCYTE
(JUVENILE)(JUVENILE) STAB (BAND; STAB (BAND;
STAFF)STAFF) MATURE MATURE
NEUTROPHIL (PMN/ NEUTROPHIL (PMN/ SEG); EOSINOPHIL; SEG); EOSINOPHIL; BASOPHILBASOPHIL
Stage where specific Stage where specific granule formation begin?granule formation begin? MYELOBLASTMYELOBLAST PROMYELOCYTEPROMYELOCYTE MYELOCYTEMYELOCYTE METAMYELOCYTE METAMYELOCYTE
(JUVENILE)(JUVENILE) STAB (BAND; STAB (BAND;
STAFF)STAFF) MATURE MATURE
NEUTROPHIL (PMN/ NEUTROPHIL (PMN/ SEG); EOSINOPHIL; SEG); EOSINOPHIL; BASOPHILBASOPHIL
Stage where nuclear Stage where nuclear indentation begin?indentation begin?
MYELOBLASTMYELOBLAST PROMYELOCYTEPROMYELOCYTE MYELOCYTEMYELOCYTE METAMYELOCYTE METAMYELOCYTE
(JUVENILE)(JUVENILE) STAB (BAND; STAB (BAND;
STAFF)STAFF) MATURE MATURE
NEUTROPHIL (PMN/ NEUTROPHIL (PMN/ SEG); EOSINOPHIL; SEG); EOSINOPHIL; BASOPHILBASOPHIL
1st stage where 1st stage where granulocytes can be granulocytes can be
classified as N E or B?classified as N E or B? MYELOBLASTMYELOBLAST PROMYELOCYTEPROMYELOCYTE MYELOCYTEMYELOCYTE METAMYELOCYTE METAMYELOCYTE
(JUVENILE)(JUVENILE) STAB (BAND; STAB (BAND;
STAFF)STAFF) MATURE MATURE
NEUTROPHIL (PMN/ NEUTROPHIL (PMN/ SEG); EOSINOPHIL; SEG); EOSINOPHIL; BASOPHILBASOPHIL
ERYTHROPOIESISERYTHROPOIESIS
PRONORMOBLASTPRONORMOBLAST BASOPHILIC NBBASOPHILIC NB POLY- CHROMAT NBPOLY- CHROMAT NB ORTHO- CHROMAT ORTHO- CHROMAT
NBNB POLYCHROMATOPHPOLYCHROMATOPH
ILIC NORMOCYTEILIC NORMOCYTE MATURE RBC; MATURE RBC;
ERYTHROCYTE; ERYTHROCYTE; DISCOCYTEDISCOCYTE
ERYTHROPOIESISERYTHROPOIESIS
RUBRIBLASTRUBRIBLAST PRORUBRICYTEPRORUBRICYTE RUBRICYTERUBRICYTE METARUBRICYTEMETARUBRICYTE RETICULOCYTERETICULOCYTE MATURE RBC; MATURE RBC;
ERYTHROCYTE; ERYTHROCYTE; DISCOCYTEDISCOCYTE
Erythrocytic SeriesErythrocytic Series Rubriblast, Pronormoblast, Erythroblast, E1Rubriblast, Pronormoblast, Erythroblast, E1 Prorubricyte, Early NB, Basophilic NB, E2Prorubricyte, Early NB, Basophilic NB, E2 Rubricyte, Intermediate NB, Polychromatic Rubricyte, Intermediate NB, Polychromatic
NB, E4NB, E4 Metarubricyte, Late NB, Orthochromatic Metarubricyte, Late NB, Orthochromatic
NB, E5NB, E5 Reticulocyte, Polychromatic NormocyteReticulocyte, Polychromatic Normocyte Erythrocyte (Normocyte, Akaryocyte, Erythrocyte (Normocyte, Akaryocyte,
Erythroplastid, Discocyte) Erythroplastid, Discocyte)
Stages capable of Stages capable of mitosis?mitosis?
PRONORMOBLASTPRONORMOBLAST BASOPHILIC NBBASOPHILIC NB POLY- CHROMAT NBPOLY- CHROMAT NB ORTHO- CHROMAT ORTHO- CHROMAT
NBNB POLYCHROMATOPHPOLYCHROMATOPH
ILIC NORMOCYTEILIC NORMOCYTE MATURE RBC; MATURE RBC;
ERYTHROCYTE; ERYTHROCYTE; DISCOCYTEDISCOCYTE
Stages capable of hgb Stages capable of hgb synthesis?synthesis?
PRONORMOBLASTPRONORMOBLAST BASOPHILIC NBBASOPHILIC NB POLY- CHROMAT NBPOLY- CHROMAT NB ORTHO- CHROMAT ORTHO- CHROMAT
NBNB POLYCHROMATOPHPOLYCHROMATOPH
ILIC NORMOCYTEILIC NORMOCYTE MATURE RBC; MATURE RBC;
ERYTHROCYTE; ERYTHROCYTE; DISCOCYTEDISCOCYTE
Stage where chromatin is Stage where chromatin is clumped?clumped?
PRONORMOBLASTPRONORMOBLAST BASOPHILIC NBBASOPHILIC NB POLY- CHROMAT NBPOLY- CHROMAT NB ORTHO- CHROMAT ORTHO- CHROMAT
NBNB POLYCHROMATOPHPOLYCHROMATOPH
ILIC NORMOCYTEILIC NORMOCYTE MATURE RBC; MATURE RBC;
ERYTHROCYTE; ERYTHROCYTE; DISCOCYTEDISCOCYTE
Stage where nucleus is Stage where nucleus is extruded out of the RBC?extruded out of the RBC?
PRONORMOBLASTPRONORMOBLAST BASOPHILIC NBBASOPHILIC NB POLY- CHROMAT NBPOLY- CHROMAT NB ORTHO- CHROMAT ORTHO- CHROMAT
NBNB POLYCHROMATOPHPOLYCHROMATOPH
ILIC NORMOCYTEILIC NORMOCYTE MATURE RBC; MATURE RBC;
ERYTHROCYTE; ERYTHROCYTE; DISCOCYTEDISCOCYTE
ErythropoiesisErythropoiesis(Pronormoblast)(Pronormoblast)
Erythropoiesis Erythropoiesis (Basophilic Normoblast)(Basophilic Normoblast)
Erythropoiesis Erythropoiesis (Polychromatophilic (Polychromatophilic
Normoblast)Normoblast)
Erythropoiesis Erythropoiesis (Orthrochromic (Orthrochromic
Normoblast)Normoblast)
Erythropoiesis Erythropoiesis (Polychromatophilic (Polychromatophilic
Erythrocyte/Reticulocyte)Erythrocyte/Reticulocyte)
ErythropoiesisErythropoiesis(Mature (Mature
Erythrocyte/RBC)Erythrocyte/RBC)
ErythropoiesisErythropoiesis
Basophilic erythroblast
Polychromatophilicerythroblast
Orthochromatophilicerythroblast Reticulocyte Mature RBC
Proerythroblast
ErythropoiesisErythropoiesis(Kinetics)(Kinetics)
RBC
Bone Marrow Differentiation
PluripotentStem Cell
MyeloidStem Cell
LymphoidStem Cell
Platelet PMN Eos Baso Mono
T-lympho
blast
B-lympho
blast
B-cell
Erythro-blast
MyeloblastMeg-blast
T-cell
Plasmacell
Monoblast
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