2 Haematopoiesis 03
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Transcript of 2 Haematopoiesis 03
HAEMATOPOIESISHAEMATOPOIESISDr Rosline HassanDr Rosline Hassan
Hematology DepartmentHematology Department
School of Medical SciencesSchool of Medical Sciences
Universiti Sains MalaysiaUniversiti Sains Malaysia
Organization of the Organization of the hematopoietic systemhematopoietic system
EmbryologyEmbryology
Anatomy of the marrowAnatomy of the marrow
Stem cellsStem cells
Marrow stromaMarrow stroma
Hematopoietic growth factorsHematopoietic growth factors
ErythropoiesisErythropoiesis
GranulopoiesisGranulopoiesis
ThrombopoiesisThrombopoiesis
HaematopoiesisHaematopoiesis
Definition : production of red blood Definition : production of red blood cells, white cells and platelets cells, white cells and platelets
175 billion red blood cells/day 175 billion red blood cells/day 70 billion granulocytes/day 70 billion granulocytes/day
(neutrophils, eosinophils, basophils) (neutrophils, eosinophils, basophils) 175 billion platelets/day 175 billion platelets/day Capable of 5-10 fold increase in Capable of 5-10 fold increase in
production production
EmbryogenesisEmbryogenesis
Dev.Dev. ageage SitesSites
FoetusFoetus 0-2 0-2 monthsmonths
Yolk sacYolk sac
2-7 2-7 monthsmonths
Liver & spleenLiver & spleen
5-9 5-9 monthsmonths
Bone marrowBone marrow
InfantsInfants Bone marrow (all bones)Bone marrow (all bones)
AdultsAdults Vetebrae, ribs, sternum, Vetebrae, ribs, sternum, sacrum, pelvis and proximal end sacrum, pelvis and proximal end of femur.of femur.
Mesoblastic phaseMesoblastic phase 2nd week - 3rd month2nd week - 3rd month Cell clusters in yolk sacCell clusters in yolk sac
Hepatic phaseHepatic phase 2nd - 6th month2nd - 6th month Mainly liver with Mainly liver with
supplementation from supplementation from spleenspleen
Myeloid phaseMyeloid phase 6th month – adult6th month – adult Red bone marrowRed bone marrow
Anatomy of Marrow Anatomy of Marrow
Volume of bone marrow at birth: Volume of bone marrow at birth: 1.5%1.5%
of body weightof body weight Volume of bone marrow as an adult:Volume of bone marrow as an adult:
4.5% of body weight4.5% of body weight
Anatomy of MarrowAnatomy of Marrow
Histology Histology Vascular CompartmentVascular Compartment Hematopoietic CompartmentHematopoietic Compartment
hematopoietic stem cellshematopoietic stem cells Precursor cellsPrecursor cells growth factor growth factor hemotopoietic microenvironment (stroma)hemotopoietic microenvironment (stroma) site for formation and maturationsite for formation and maturation
Cellularity 30-70% Cellularity 30-70%
Haematopoietic cellsHaematopoietic cells
Stem Cells Stem Cells Pluripotential Stem Cells Pluripotential Stem Cells
Self Renewal Self Renewal DifferentiationDifferentiation ProliferationProliferation
Multipotential Stem Cells – ( Lymphoid, Multipotential Stem Cells – ( Lymphoid, Myeloid Stem Cells)Myeloid Stem Cells)
Progenitor Cells - CFU's (Colony Forming Progenitor Cells - CFU's (Colony Forming Units)Units)
Haematopoietic cellsHaematopoietic cells
Precursor Cells - Blasts and their Precursor Cells - Blasts and their progeny progeny First morphologically identifiable cells First morphologically identifiable cells
Normoblast - Red Cells Normoblast - Red Cells Myeloblast – GranulocytesMyeloblast – Granulocytes Monoblast – MonocytesMonoblast – Monocytes Lymphoblast – LymphocytesLymphoblast – Lymphocytes Megakaryoblast - PlateletsMegakaryoblast - Platelets
Little if any self-renewalLittle if any self-renewal
Haematopoietic cellsHaematopoietic cells
Mature Effector CellsMature Effector Cells Red Cells – carry oxygen, carbon Red Cells – carry oxygen, carbon
dioxide; lifespan 120 daysdioxide; lifespan 120 days Neutrophils – phagocytosis, killing Neutrophils – phagocytosis, killing Monocytes – phagocytosis, killing, Monocytes – phagocytosis, killing,
antigen presentationantigen presentation Lymphocytes – immune responseLymphocytes – immune response Platelets – haemostasisPlatelets – haemostasis
MicroenvironmentMicroenvironmentForms a suitable environmentForms a suitable environment forfor stem cell stem cell growth and development.growth and development.
Composed of stromal cells & a microvascular Composed of stromal cells & a microvascular networknetwork
Bone Marrow Stromal CellsBone Marrow Stromal Cells - key role in marrow - key role in marrow Fibroblasts, fat cells, endothelial cells, reticulum Fibroblasts, fat cells, endothelial cells, reticulum
cells and macrophagecells and macrophage Express Adhesion Molecules Express Adhesion Molecules Secrete Growth FactorsSecrete Growth Factors and extracellular molecules and extracellular molecules
(collagen, glycoproteins & glycosaminoglycans) (collagen, glycoproteins & glycosaminoglycans) forming extracellular matrixforming extracellular matrix
Stromal matrixStromal matrix Physical Support for Hematopoietic Cells Physical Support for Hematopoietic Cells
Haemopoiesis occur within Haemopoiesis occur within microenvironmentmicroenvironment
Stem cells are in contact Stem cells are in contact with other cellwith other cell
(e.g macrophage, (e.g macrophage, fibroblast)fibroblast)
Cell-cell communication isCell-cell communication is
by binding via cell surface by binding via cell surface receptors, to adhesion receptors, to adhesion molecules & secretion of molecules & secretion of cytokines & GFs cytokines & GFs
These binding lead to These binding lead to proliferation, proliferation, differentiation & apoptosisdifferentiation & apoptosis
Haematopoietic Growth Haematopoietic Growth FactorsFactors
Glycoprotein hormonesGlycoprotein hormones Function :Function : Progenitor cellsProgenitor cells
ProliferationProliferation DifferentiationDifferentiation MaturationMaturation
Act – locally or circulate Act – locally or circulate in plasmain plasma
Produced by :Produced by : lymphocyteslymphocytes monocytesmonocytes macrophagesmacrophages
e.g : IL-1, TNF, IL-3, erythropoietine.g : IL-1, TNF, IL-3, erythropoietin
Mature blood cellsMature blood cells Functional activationFunctional activation Prevention of apoptosisPrevention of apoptosis
endothelial cells endothelial cells fibroblastsfibroblasts
ClassificationClassification Non lineage specific GFNon lineage specific GF
Act on pluripotential & Act on pluripotential & multipotential stem cells to multipotential stem cells to initiate self renewal & initiate self renewal & differentiationdifferentiation
e.g :IL-3, GM-CSFe.g :IL-3, GM-CSF Lineage specific GFLineage specific GF
Act on progenitor cells, involve in Act on progenitor cells, involve in differentiation & maturation of differentiation & maturation of cells cells
e.g :CSF, M-CSF, erythropoetin e.g :CSF, M-CSF, erythropoetin & thrombopoietin& thrombopoietin
Lymphokine and Lymphokine and monokinesmonokines Release by lymphocytes & Release by lymphocytes &
monocytes monocytes e.g : interleukin-1 (IL-1)e.g : interleukin-1 (IL-1)
HaematopoiesisHaematopoiesis
ErythropoiesisErythropoiesis Occurs near the sinus apertures Occurs near the sinus apertures Seen as erythroblastic islands surround Seen as erythroblastic islands surround
the macrophages the macrophages Matured red cell squeeze through the Matured red cell squeeze through the
aperture leaving their nuclei behindaperture leaving their nuclei behind GranulopoiesisGranulopoiesis
Occurs deep in the cordsOccurs deep in the cords Mature cells become motile at the Mature cells become motile at the
metamyelocyte stagemetamyelocyte stage
LymphopoiesisLymphopoiesis Leave the bone marrow and complete Leave the bone marrow and complete
differentiation in the lymph nodes (B differentiation in the lymph nodes (B cells) and thymus (T cells)cells) and thymus (T cells)
ThrombopoiesisThrombopoiesis Occurs along the outside surface of the Occurs along the outside surface of the
vascular sinuses vascular sinuses Release strings of cytoplasmic platelet Release strings of cytoplasmic platelet
directly into the circulation. directly into the circulation.
ErythropoiesisErythropoiesis
RBC development takes about 7 daysRBC development takes about 7 days Involves 3 to 4 mitotic cell divisionsInvolves 3 to 4 mitotic cell divisions Each stem cell gives rise to 8 or 16 cellsEach stem cell gives rise to 8 or 16 cells Stages of RBC development characterized byStages of RBC development characterized by
1.1. gradual appearance of haemoglobingradual appearance of haemoglobin
2.2. disappearance of ribonucleic acid (RNA)disappearance of ribonucleic acid (RNA)
3.3. progressive degeneration of nucleusprogressive degeneration of nucleus
4.4. gradual loss of cytoplasmic organelles e.g gradual loss of cytoplasmic organelles e.g mitochondriamitochondria
5.5. gradual reduction in cell sizegradual reduction in cell size
Substances required for erythropoiesis :Substances required for erythropoiesis :
i. Metal (e.g: iron, mangenese & cobalt)i. Metal (e.g: iron, mangenese & cobalt)
ii. Vitamin (e.g: Bii. Vitamin (e.g: B1212, Folate, Vit C, Vit E, Vit , Folate, Vit C, Vit E, Vit
BB6 6 (pyridoxine), thiamine, (pyridoxine), thiamine,
riboflavin riboflavin & pantothenic acid)& pantothenic acid)
iii. Amino acidiii. Amino acid
iv.iv. Hormones (e.g: stem cell factor, IL-3, Hormones (e.g: stem cell factor, IL-3, GM-GM- CSF, erythropoietin, CSF, erythropoietin, androgen androgen & thyroxine)& thyroxine)
Life cycle of RBCsLife cycle of RBCs
1.1. Kidneys respond to lower Kidneys respond to lower oxygen concentration in blood oxygen concentration in blood releasing erythropoietin (EPO). releasing erythropoietin (EPO).
2.2. EPO travels to red marrow and EPO travels to red marrow and stimulates production of RBCs stimulates production of RBCs
3.3. Red marrow produces RBCs Red marrow produces RBCs from stem cellsfrom stem cells
4.4. RBCs squeeze through vessel RBCs squeeze through vessel membrane to enter circulationmembrane to enter circulation
5.5. Heart and lungs work to Heart and lungs work to supply oxygenation of RBCs. supply oxygenation of RBCs.
6.6. Damaged or old RBCs Damaged or old RBCs destroyed by the spleen.destroyed by the spleen.
LeukopoiesisLeukopoiesis
Leukopoiesis (white blood cell Leukopoiesis (white blood cell formation) encompasses both formation) encompasses both granulopoiesis and agranulopoiesis. granulopoiesis and agranulopoiesis.
Granulopoiesis occurs in the bone Granulopoiesis occurs in the bone marrow of healthy adults.marrow of healthy adults.
Kinetics of Neutrophil Production - 14 Kinetics of Neutrophil Production - 14 days from myeloblast to neutrophil.days from myeloblast to neutrophil.
GranulopoiesisGranulopoiesis
3 types of granulocytes (derive from a 3 types of granulocytes (derive from a single precursor CFU-G)single precursor CFU-G)
NeutrophilsNeutrophils BasophilsBasophils EosinophilsEosinophils
The structural changes include The structural changes include 1.1. Decrease in cell sizeDecrease in cell size
2.2. Condensation of nuclear chromatinCondensation of nuclear chromatin
3.3. Changes in nuclear shape (flattening Changes in nuclear shape (flattening →→ indentation indentation →→ lobulation lobulation
4.4. Accumulation of cytoplasmic granulesAccumulation of cytoplasmic granules
Stages of maturation :Stages of maturation :
1.1. MyeloblastMyeloblast2.2. Promyelocyte Promyelocyte (1(10 0
granules)granules)
3.3. Myelocyte (Myelocyte (220 0 granules)granules) Last mitotically active Last mitotically active
stage in granulopoiesis.stage in granulopoiesis.
4.4. MetamyelocyteMetamyelocyte
5.5. Band neutrophil / stab Band neutrophil / stab formform
LymphopoiesisLymphopoiesis
Production of lymphocytes.Production of lymphocytes. Lymphoid stem cells give rise to the major Lymphoid stem cells give rise to the major
functional classes of lymphocytes :functional classes of lymphocytes :
i. B cells (Undergo differentiation to i. B cells (Undergo differentiation to become become plasma cells and plasma cells and produce produce immunoglobulin.immunoglobulin.
ii. T cellsii. T cells
iii. NK cellsiii. NK cells
Arise from progenital cells responsible for Arise from progenital cells responsible for the production of granulocytes, the production of granulocytes, monocytes, red blood cells & platelet monocytes, red blood cells & platelet
The differentiation involve :The differentiation involve : acquisitionacquisition loss of series of surface antigen loss of series of surface antigen defined by defined by monoclonal antibodies.monoclonal antibodies.
Antigen Independent PhaseAntigen Independent Phase Initial lymphopoiesis takes place in bone marrow Initial lymphopoiesis takes place in bone marrow Maturation takes places in lymph nodes or Maturation takes places in lymph nodes or
thymus thymus Antigen Dependent PhaseAntigen Dependent Phase
Second cycle of differentiation and proliferation Second cycle of differentiation and proliferation in response to antigen exposure in response to antigen exposure
Antibody and Hematopoietic Growth Hormone Antibody and Hematopoietic Growth Hormone Production Production
Memory Phase Memory Phase Follows antigen exposureFollows antigen exposure May live for years May live for years
ThrombopoiesisThrombopoiesis
Production of platelet.Production of platelet. Platelet are shed from the cytoplasm Platelet are shed from the cytoplasm
of megakaryocytes.of megakaryocytes. Megakaryocytes developed in the Megakaryocytes developed in the
bone marrow from the bone marrow from the megakaryocyte colony forming units megakaryocyte colony forming units (CFU-Mega) also derived from (CFU-Mega) also derived from pluripotential stem cells. pluripotential stem cells.
Megakaryocytes maturation :Megakaryocytes maturation :
1.1. Endomitotic synchronous nuclear replication Endomitotic synchronous nuclear replication (nucleus divides, not cell - max 64 segments)(nucleus divides, not cell - max 64 segments)
2.2. Enlarging cytoplasmic volume Enlarging cytoplasmic volume
3.3. Cytoplasm become granularCytoplasm become granular
4.4. Demarcation of membrane of individual Demarcation of membrane of individual plateletsplatelets
Individual platelet or larger fragments are broken Individual platelet or larger fragments are broken off & carried by blood to lungs where the off & carried by blood to lungs where the breakdown is completed in pulmonary circulationbreakdown is completed in pulmonary circulation..
They circulate for 6-8 days, then destroyed in They circulate for 6-8 days, then destroyed in spleen or pulmonary vascular bed.spleen or pulmonary vascular bed.
Summary Summary Haematopoiesis is a process of blood cells productionHaematopoiesis is a process of blood cells production It begins very early in prenatal period and continues till adultIt begins very early in prenatal period and continues till adult The process requiresThe process requires
Stem cellsStem cells MicroenvironmentMicroenvironment
Stromal cellsStromal cells Stromal MatrixStromal Matrix
Other substancesOther substances Stem cells undergo differentiation & self renewal Stem cells undergo differentiation & self renewal Progenitor cells undergo differentiation and maturationProgenitor cells undergo differentiation and maturation Mature cells release into blood circulationMature cells release into blood circulation Most of cells will reenter the tissue phase and undergo Most of cells will reenter the tissue phase and undergo
apoptosisapoptosis