hemopoiesis

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Hemopoiesis

• Prasit Chanarat
• Clinical microscopy AMS. CMU.

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HEMOPOIESIS

• Objectives
• 1. Describe the ontogeny of hemopoiesis
• 2. Discuss the theories of hemopoiesis
• 3. Discuss the totipotential stem cells,
  committed stem cells, progenitor sells,
  precursor cells
• 4. Discuss a regulation of hemopoiesis and
• hemopoietic proliferation
• 5. Describe composition and function of blood

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Whole Blood

• Fluid - Plasma
• Cell - WBC (Leukocytes)
• - Platelets (Thrombocytes)
• - RBC (Erythrocytes)
• Clotted blood ----- Serum
• Anticoagulated blood ----- Plasma
• Fibrinogen ----(thrombin)-gt Fibrin
• Antocoagulants EDTA, Heparin
• EDTA removes Ca2
• Heparin neutralizes thrombin

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Plasma

• Protein Albumin, Globulin (alpha-1, alpha-2,
  Beta, gamma), fibrinogen, clotting factors
• (Coagulation factors)
• Amino acids, peptides, glucose, lipids, lactic
  acid,
• enzymes, vitamins, hormones, BUN, uric acid,
  
• creatinine, electrolytes (Na, K, Ca2, Mg2,
  Ci-, HCO3-, SO4-2, etc.)

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Hemopoiesis

• Hemapoiesis (Hematopoiesis)
• Hemo Hemato Blood
• Poiesis Production
• Hemopoiesis system
• Bone marrow, spleen, liver, thymus, lymphnode

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Hematopoiesis

• Production and Development of Blood Cells
• Pluripotent Stem Cell
• - Continuous Self-Replication
• - Gives Rise to All Blood Cell Lines
• Growth Factors (Cytokines) - Promote
  Differentiation Into Mature Blood Elements

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Hemopoiesis Phases

• 1. Embryonic or prenatal phase
• - mesoblastic peroid
• - hepatic period
• - myeloid period
• 2. Post-natal phase
• - medullary hemopoiesis
• - extramedullary hemopoiesis

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Hemopoiesis

• PHSC CSC Diff. Compartment
  Circulation
• lt------ Proliferation ---------------------gt
• Differentiation
  --------------------gt
• Maturation
  -----------------------gt
• Release
  -------------------------gt
• PHSC Pluripotent hemopoietic stem cells
• CSC Committed stem cells

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Theories of Hemopoiesis

• I. Monophyletic theory
• Totipotential stem cells
• II Polyphyletic theory
• Dualists
• Trialists
• Polyphyletists

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Stem Cells and theirTherapeutic Potential
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What are stem cells?
Stem cells
Embryonic
Adult
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The defining properties of a stem cell

• It is not terminally differentiated.
• It can divide without limit.
• When it divides, the daughter cell has 2
  choices
• Remain a stem cell.
• Terminally differentiate.

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Varying Potentials of Stem Cells

• Totipotent cells. Fertilized oocyte (zygote)
  progeny of the first two cell divisions. Cells
  able to form the whole organism.
• Pluripotent cells. Obtained from the inner cell
  mass of the blastocyst, able to differentiate
  into almost all cells of the three germ layers
  but not into an embryo.
• Multipotential cells. Found in most tissues,
  these cells can produce a limited range of
  differentiated cell lineages appropriate to their
  location (e.g., Hematopoietic stem cells from the
  bone marrow).
• Unipotential cells. Cells capable of generating
  only one cell type (epidermal stem cells, adult
  liver stem cells).

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Leukopoiesis
Objective 1. Classification of WBC 2.
Leukopoiesis 2.1 Granulopoiesis 2.2
Monopoiesis 2.3 Lymphopoiesis 2.4
Plasmopoiesis 3. Factors affecting leukopoiesis

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Classification of WBC
1. Shape of the nucleus 1.1 mononuclear
Lymphocyte, Monocyte 1.2 Polymorphonuclear
PMN, Eos, Baso 2. Granules 2.1
Granulocytes PMN, Eos, Baso 2.2
Agranulocyte Lymphocyte, Monocyte 3. Site of
origin Myeloid cells / Lymphoid
cells 4. Function / Phagocyte
Macrophage - Monocyte Microphage -
PMN

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Leukopoiesis Study

1. Morphology 2. Biochemical markers 3.
Immunological markers 4. Gene markers



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Stage of Granulopoiesis
Stem cell
Myeloblast

Promyelocyte Basophilic
Neutrophilic Eosinophilic
Myelocyte Myelocyte
Myelocyte Metamyelocyte
Metamyelocyte Metamyelocyte Band
Band
Band Basophil Neutrophil
(PMN) Eosinophil

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Regulation of Neutrophil Production
Bone Marrow Blood stream
Tissue Proliferatrion Circulating
Move freely compartment
compartment Storage
Marginating Move compartment
compartment restricted
(Area
of infection)
Release control

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Neutropenia PMN decrease Neutrophilia
PMN increase Cytokine Multi-CSF
(IL-3) GM-CSF
G-CSF
IL-6
Granulopoietin (Granulocytic
growth factor)

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Eosinophilia Eos. increase Cytokine
IL-3 IL-5
GM-CSF
ECF-A (Eosinophilic chemotactic
factor of
anaphylaxis)

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Basophilia Baso. increase Cytokine
GM-CSF IL-4
IL-9

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Monopoiesis
Stem cell
Monoblast
Promonocyte
Monocyte

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Monocytosis Monocyte increase Cytokine
IL-3 GM-CSF
M-CSF

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Tissue macrophage
Osteoclast Bone Macrophage Lymphoid
tissue Kupffer cell Liver Microglia cell
Brain Serosal macrophage Pleural
cavity Alveolar macrophage Lung

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Lymphopoiesis

• Within thymus is not antigen dependent
• Within lymphnode / spleen mediated by
• antigen stimulation
• - molecular nature of antigen
• - antigen dose
• - circulating antibody levels
• - handling of antigen by RE cells
• - proliferation of thymus-derived cells
• - thymic humoral factors

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Central Lymphoid Peripheral
Lymphoid Thymus T-lymph
CMI Stem Th
Ts cells Bursal
B-lymph Plasma cell
equivalent
HMI

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Stage of T-cell differentiation
Thymic cortex - Stage I (Early thymocyte)
- Stage II (Common
thymocyte) Thymic medulla - Stage III (Late
thymocyte) Peripheral blood - Mature cell
- Activated T-cell (See
picture of Immunophenotype of Ontogeny T-cell)

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Biochemical marker
Thymocyte
Stage I II
III T-cell TdT
- ADA
PNP

dCK
5NT
/- Tdt Terminal
deoxytransferase ADA Adenosine deaminase PNP
Purine nucleoside phosphorylase dCK
Deoxycytidine kinase 5NT 5-Nucleotidase

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Molecular Marker
Thymocyte
Stage I II
III T-cell TCR- beta rearr.
-------------------------- TCR- beta mRNA
------------------- TCR-gamma gene
rearr. -------------------------- TCR-gamma mRNA
--------- TCR-alpha mRNA
------------------- CD3 mRNA
-------------------------- Cytoplasmic CD3
-------------------- Surface CD3/TCR
-----------

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Stage of Human B-cell
Stem cell Pre-B Resting Activated
Proliferating Differentiating Secretory

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Plasmopoiesis

B-cell Plasmoblast (Plasmablast) Proplasmocyte
(Proplasmacyte) Plasma cell



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Lymphocyte Growth Factor
Cytokine Cell
Function IL-1 Monocyte
T-cell activation IL-2
T-cell Proliferation of
activated
T-cell IL-3 T-cell
For T-cell subset
and myeloid cell BGCF
T-cell For B-cell
BCDF T-cell For B-cell
Ig synthesis

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Factors Affecting Lymphopoiesis

• Age
• Diet
• Steroid - Testosterone
• Thyroxine
• Thymosine
• Infection - Viral
• - Bacterial - Pertussis
• - Chronic disease - TB

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Factors Affecting Lymphopoiesis

• Age
• Diet
• Steroid - Testosterone
• Thyroxine
• Thymosine
• Infection - Viral
• - Bacterial - Pertussis
• - Chronic disease - TB

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Erythroid Maturation Sequence
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Hemopoietic progenitor cells

• CFU-GEMM (Granulocyte, erythrocyte, monocyte,
• megakaryocyte)
• CFU-GM (Granulocyte, monocyte)
• CFU-Eo (Eosinophil)
• CFU-Baso (Basophil)
• CFU-Meg (Megakaryocyte)
• BFU-E (Erythrocyte)
• CFU-E (Erythrocyte)
• CFU Colony forming unit BFU Burst
  forming unit

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Hemopoietic growth factors

• A family of hormones
• As cytokines
• Regulatation
• - proliferation
• - differentiation
• - maturation of progenitor cells
• - survival and function of mature cells
• Hemopoietin

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Cytokines

• Produced by
• - monocyte - fibroblast
• - lymphocyte - endothelial
  cells
• Act several target cells
• - fibroblast -
  hemopoietic cell
• - lymphoid cell - hepatocyte
• - endocrine cell

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Cytokines Family

• Interferons
• - IFN-alpha, IFN-beta, IFN-gamma
• Interleukins
• - IL-1, IL-2, IL-3, IL-4, . IL-15
• CSF (Colony stimulating factors)
• - G-CSF, GM-CSF, M-CSF, EPO
• Growth factors
• - TGF-beta-1, TGF-beta-2, . TFG-beta-5
• - EGF, FGF
• (T transforming, E epidermal, F
  fibroblast)

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Cellular Cytokines Production (1)

• Endothelial cells
• - GM-CSF, G-CSF, M-CSF, IL-6
• Macrophage
• - GM-CSF, G-CSF, M-CSF, IL-3, IL-6, EPO,
  SCF
• T cells
• - GM-CSF, IL-2, IL-3, IL-4, IL-5
• Fibroblast
• - GM-CSF, G-CSF, M-CSF, IL-6, SCF

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Cellular Cytokines Production (2)

• NK cells - GM-CSF
• PMN - G-CSF, GM-CSF
• B cells
• - GM-CSF, M-CSF, IL-2, IL-5, IL-6
• Marrow stroma
• - GM-CSF, G-CSF, M-CSF, IL-6, IL-3, SCF,
  IL-11
• Renal parenchyma, Liver, Bone marrow
• - EPO

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Control Mechanism of Hemopoiesis

• Depend on
• 1. Nature cells
• 2.Humoral factors EPO, Granulopoietin,
  thrombopoietin, CSF, GM-CSF, IL-1, Cytokines,
  etc.
• 3. Cell-cell interaction
• 4. Pharmacologic substances Chalone (inhibit
• stem cells)

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THE END