02 hematopoiesis

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