HEMATOPOIESIS dr Sri Lestari Sulistyo Rini MSc Hematopoiesis

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HEMATOPOIESIS dr Sri Lestari Sulistyo Rini, MSc

HEMATOPOIESIS dr Sri Lestari Sulistyo Rini, MSc

Hematopoiesis • Hematopoiesis (hemopoiesis): blood cell formation – Occurs in red bone marrow of

Hematopoiesis • Hematopoiesis (hemopoiesis): blood cell formation – Occurs in red bone marrow of axial skeleton, girdles and proximal epiphyses of humerus and femur

Hematopoiesis • Hemocytoblasts (hematopoietic stem cells) – Give rise to all formed elements –

Hematopoiesis • Hemocytoblasts (hematopoietic stem cells) – Give rise to all formed elements – Hormones and growth factors push the cell toward a specific pathway of blood cell development • New blood cells enter blood sinusoids

Hematopoiesis: • Stem cells in bone marrow • proliferate • differentiate • mature •

Hematopoiesis: • Stem cells in bone marrow • proliferate • differentiate • mature • myeloid vs. lymphoid • Stromal cells secrete growth factors • Cytokines signal via membrane receptors

Bone marrow • Bone marrow stromal cells secrete growth factors • Hematopoietc stem cells

Bone marrow • Bone marrow stromal cells secrete growth factors • Hematopoietc stem cells respond

Stem cells Hemocytoblast Lymphoid stem cell Myeloid stem cell Committed cells Developmental pathway Myeloblast

Stem cells Hemocytoblast Lymphoid stem cell Myeloid stem cell Committed cells Developmental pathway Myeloblast Monoblast Lymphoblast Promyelocyte Promonocyte Promyelocyte Eosinophilic myelocyte Basophilic myelocyte Neutrophilic myelocyte Eosinophilic band cells Basophilic band cells Neutrophilic band cells Monocytes Eosinophils Basophils Neutrophils (a) (b) (c) (d) Granular leukocytes Prolymphocyte Lymphocytes (e) Agranular leukocytes Some become

Blood Cell Production

Blood Cell Production

Hematopoiesis involves cytokine signaling Growth factors signal through membrane receptors: • Ligand causes receptors

Hematopoiesis involves cytokine signaling Growth factors signal through membrane receptors: • Ligand causes receptors to aggregate • Activates JAK (kinases) by phosphorylation (cytoplasmic RTK) • JAK phophorylates cytokine receptor on Tyr

Hematopoiesis involves cytokine signaling • Other signaling molecules bind, including STAT (signal transducer and

Hematopoiesis involves cytokine signaling • Other signaling molecules bind, including STAT (signal transducer and activator of transcription) → nucleus transcription • Also RAS/Raf/MAP kinase activated • Overactive signal → cancer • Transient signal: SOCS silences

Normal Marrow Composition unidentified or disintegrated cells erythroid precursors 10% Lymphocytes, monocytes 20% 10%

Normal Marrow Composition unidentified or disintegrated cells erythroid precursors 10% Lymphocytes, monocytes 20% 10% 60% granulocytes & precursors

Hematopoietic Growth Factors (SCF, IL-6, GM-CSF, etc. ) • glycoprotein hormones • secreted by

Hematopoietic Growth Factors (SCF, IL-6, GM-CSF, etc. ) • glycoprotein hormones • secreted by – bone marrow stromal cells – T-cells monocytes • regulate division and differentiation of hematopoietic cells • responsible for basal hematopoiesis and maintaining blood counts in normal ranges • greatly increased secretion in response to infection

Erythropoiesis • erythropoietin-independent stage: – GM-CSF – SCF marrow stromal cells IL-3 (activated T-cells)

Erythropoiesis • erythropoietin-independent stage: – GM-CSF – SCF marrow stromal cells IL-3 (activated T-cells) • erythropoietin-dependent stage: – erythropoietin hypoxia(liver, kidney)

Granulopoiesis • early phase: • • GM-CSF SCF Neutropoiesis: G-CSF Monopoiesis: Eosinopoiesis: M-CSF IL-5

Granulopoiesis • early phase: • • GM-CSF SCF Neutropoiesis: G-CSF Monopoiesis: Eosinopoiesis: M-CSF IL-5 IL-3 Basopoiesis, Mastpoiesis: IL-3 GM-CSF SCF IL-3

Megakaryopoiesis IL-3 SCF GM-CSF • may also play a role IL-6

Megakaryopoiesis IL-3 SCF GM-CSF • may also play a role IL-6

Lymphopoiesis • B-cells: – initial stage: – later stage: IL-7 SCF Fcg rec IL-4

Lymphopoiesis • B-cells: – initial stage: – later stage: IL-7 SCF Fcg rec IL-4 IL-6 – final proliferation and Ab secretion: • T-cells: • CD 8 cells: • CD 4 cells: IL-6 IL-2 Ag TCR/CD 3 CD 28 GM-CSF

Hematopoietic Growth Factors (IL-6, GM-CSF, SCF, etc. ) • Bacterial & viral products •

Hematopoietic Growth Factors (IL-6, GM-CSF, SCF, etc. ) • Bacterial & viral products • monocyte T-cell IL-1 TNFa G-CSF M-CSF GM-CSF IL-3 Fibroblast Endothelial cell IL-6 GM-CSF G-CSF

Hematopoietic Microenvironment Stromal cells: fibroblasts endothelial cells adipocytes Growth Factors

Hematopoietic Microenvironment Stromal cells: fibroblasts endothelial cells adipocytes Growth Factors

Basal Hematopoiesis SCF IL-6 GM-CSF G-CSF SCF: stem cell factor GM-CSF: granulocyte-macrophage colony-stimulating factor

Basal Hematopoiesis SCF IL-6 GM-CSF G-CSF SCF: stem cell factor GM-CSF: granulocyte-macrophage colony-stimulating factor G-CSF: granulocyte colony-stimulating factor

Antigen-amplified hematopoiesis TNFa IL-1 Ag TNFa IL-3 GM-CSF IL-4 SCF IL-6 GM-CSF G-CSF

Antigen-amplified hematopoiesis TNFa IL-1 Ag TNFa IL-3 GM-CSF IL-4 SCF IL-6 GM-CSF G-CSF

Erythropoiesis • Erythropoiesis: red blood cell production – A hemocytoblast is transformed into a

Erythropoiesis • Erythropoiesis: red blood cell production – A hemocytoblast is transformed into a proerythroblast – Proerythroblasts develop into early erythroblasts

Erythropoiesis – Phases in development 1. Ribosome synthesis 2. Hemoglobin accumulation 3. Ejection of

Erythropoiesis – Phases in development 1. Ribosome synthesis 2. Hemoglobin accumulation 3. Ejection of the nucleus and formation of reticulocytes – Reticulocytes then become mature erythrocytes

RBC Formation before birth • Mesoblastic stage – Nucleated RBCs - Yolk sac and

RBC Formation before birth • Mesoblastic stage – Nucleated RBCs - Yolk sac and Mesothelial layers of the placenta – 3 rd week • Hepatic stage • At 6 weeks - Liver form blood cells – Spleen + lymphoid tissues form blood cells.

RBC Formation before birth • Myeloid stage • From the third month onwards -

RBC Formation before birth • Myeloid stage • From the third month onwards - the bone marrow gradually becomes the principal source of the RBCs • Last month – Bone marrow exclusively

RBC Formation after birth • The bone marrow - all bones - 5 years

RBC Formation after birth • The bone marrow - all bones - 5 years • Marrow of the long bones (except for the proximal humerus and tibia) – No more red blood cells after = age 20 years. • Most red cells continue to be produced in the marrow of the membranous bones, such as – Vertebrae, Sternum, Ribs, and Ilium.

Relative rates of red blood cell production in the bone marrow of different bones

Relative rates of red blood cell production in the bone marrow of different bones at different ages.

Bone marrow cells for Erythropoiesis • Pluripotential hematopoietic stem cell, PHSC • Committed stem

Bone marrow cells for Erythropoiesis • Pluripotential hematopoietic stem cell, PHSC • Committed stem cell that produces erythrocytes is called Colony-forming unit–erythrocyte, CFU-E Factors: – Growth inducers – Differentiation inducers.

ERYTHROPOIESIS PHSC CFU-E Bone marrow 4 -5 days Proerythroblast Polychromatophil erythroblast Orthochromatophil erythroblast Reticulocyte

ERYTHROPOIESIS PHSC CFU-E Bone marrow 4 -5 days Proerythroblast Polychromatophil erythroblast Orthochromatophil erythroblast Reticulocyte Erythrocyte. Blood 1 -2 days.

Erythropoiesis – Phases in development 1. Ribosome synthesis in early erythroblasts 2. Hemoglobin accumulation

Erythropoiesis – Phases in development 1. Ribosome synthesis in early erythroblasts 2. Hemoglobin accumulation in late erythroblasts and normoblasts 3. Ejection of the nucleus from normoblasts and formation of reticulocytes – Reticulocytes then become mature erythrocytes – 1 -2 % of all circulating erythrocytes

Stem cell Hemocytoblast Committed cell Developmental pathway Proerythroblast Early Late erythroblast Phase 1 Ribosome

Stem cell Hemocytoblast Committed cell Developmental pathway Proerythroblast Early Late erythroblast Phase 1 Ribosome synthesis Phase 2 Hemoglobin accumulation Phase 3 Ejection of nucleus Normoblast Reticulo- Erythrocyte

Regulation of Erythropoiesis • Too few RBCs leads to tissue hypoxia • Too many

Regulation of Erythropoiesis • Too few RBCs leads to tissue hypoxia • Too many RBCs increases blood viscosity • Balance between RBC production and destruction depends on • Hormonal controls : Erythropoietin (EPO) – Direct stimulus for erythropoiesis – Released by the kidneys in response to hypoxia – Adequate supplies of iron, amino acids, and B vitamins

Hormonal Control of Erythropoiesis • Effects of EPO – More rapid maturation of committed

Hormonal Control of Erythropoiesis • Effects of EPO – More rapid maturation of committed bone marrow cells – Increased circulating reticulocyte count in 1– 2 days • Testosterone also enhances EPO production, resulting in higher RBC counts in males

Hormonal Control of Erythropoiesis • Causes of hypoxia – Hemorrhage or increased RBC destruction

Hormonal Control of Erythropoiesis • Causes of hypoxia – Hemorrhage or increased RBC destruction reduces RBC numbers – Insufficient hemoglobin (e. g. , iron deficiency) – Reduced availability of O 2 (e. g. , high altitudes)

Erythropoietin Mechanism Imb ala nce Start Normal blood oxygen levels Imb ala nce Increases

Erythropoietin Mechanism Imb ala nce Start Normal blood oxygen levels Imb ala nce Increases O 2 -carrying ability of blood Stimulus: Hypoxia due to decreased RBC count, decreased availability of O 2 to blood, or increased tissue demands for O 2 Reduces O 2 levels in blood Enhanced erythropoiesis increases RBC count Erythropoietin stimulates red bone marrow Kidney (and liver to a smaller extent) releases erythropoietin Figure 17. 6

Dietary Requirements for Erythropoiesis • Nutrients—amino acids, lipids, and carbohydrates • Iron – Stored

Dietary Requirements for Erythropoiesis • Nutrients—amino acids, lipids, and carbohydrates • Iron – Stored in Hb (65%), the liver, spleen, and bone marrow – Stored in cells as ferritin and hemosiderin – Transported loosely bound to the protein transferrin • Vitamin B 12 and folic acid—necessary for DNA synthesis for cell division

(a) Normal erythrocyte has normal hemoglobin amino acid sequence in the beta chain. 1

(a) Normal erythrocyte has normal hemoglobin amino acid sequence in the beta chain. 1 2 3 4 5 6 7 146 (b) Sickled erythrocyte results from a single amino acid change in the beta chain of hemoglobin.

Formation & Destruction of RBCs

Formation & Destruction of RBCs

Leukopoiesis • Production of WBCs • Stimulated by chemical messengers from bone marrow and

Leukopoiesis • Production of WBCs • Stimulated by chemical messengers from bone marrow and mature WBCs – Interleukins (e. g. , IL-1, IL-2) – Colony-stimulating factors (CSFs) named for the WBC type they stimulate (e. g. , granulocyte-CSF stimulates granulocytes) • All leukocytes originate from hemocytoblasts

Production of Leukocytes • Leukopoiesis is hormonally stimulated by two families of cytokines (hematopoietic

Production of Leukocytes • Leukopoiesis is hormonally stimulated by two families of cytokines (hematopoietic factors) – interleukins and colony-stimulating factors (CSFs) • Macrophages and T cells are the most important sources of cytokines • Many hematopoietic hormones are used clinically to stimulate bone marrow

Formation of Leukocytes • All leukocytes originate from hemocytoblasts – The mother of all

Formation of Leukocytes • All leukocytes originate from hemocytoblasts – The mother of all blood stem cells • Hemocytoblasts differentiate into myeloid stem cells and lymphoid stem cells – Myeloid stem cells become myeloblasts or monoblasts • Granulocytes form from myeloblasts • Monoblasts enlarge and form monocytes – Lymphoid stem cells become lymphoblasts • Lymphoblasts develop into lymphocytes

Platelets • • Small fragments of megakaryocytes Formation is regulated by thrombopoietin Blue-staining outer

Platelets • • Small fragments of megakaryocytes Formation is regulated by thrombopoietin Blue-staining outer region, purple granules Granules contain serotonin, Ca 2+, enzymes, ADP, and platelet-derived growth factor (PDGF)

Platelets • Form a temporary platelet plug that helps seal breaks in blood vessels

Platelets • Form a temporary platelet plug that helps seal breaks in blood vessels • Circulating platelets are kept inactive and mobile by NO and prostacyclin from endothelial cells of blood vessels

Stem cell Developmental pathway Hemocytoblast Promegakaryocyte Megakaryoblast Megakaryocyte Platelets

Stem cell Developmental pathway Hemocytoblast Promegakaryocyte Megakaryoblast Megakaryocyte Platelets

Lifespan of blood cells • RBC • platelet 120 days 10 days • granulocytes

Lifespan of blood cells • RBC • platelet 120 days 10 days • granulocytes circ : 9 hours • tissue : days • lymphocyte • circ : variable (hours to years) tissue : weeks to years

Hematopoietic Response hypoxia RBC infection granulocyte/monocyte antigen lymphocyte hemorrhage platelet

Hematopoietic Response hypoxia RBC infection granulocyte/monocyte antigen lymphocyte hemorrhage platelet

TERIMA KASIH

TERIMA KASIH