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Haemopoiesis

What is it?
1. Refers to the production of all the cells of the blood
  1. Can be further split into
    1. Erythropoiesis (RBCs)
    2. Leukopoiesis (WBCs)
    3. Thrombopoiesis (thrombocytes, aka platelets)
  2. Begins during the 20th week of life in the foetal liver and spleen - this role is then taken over by the bone marrow in the young on into adulthood
The bone marrow
1. i.e. the site of haemopoiesis (in adults) - restricted to the proximal regions of long bones and the support skeleton
2. Develops in the embryo - from hollowing out of the long bones (forming a central cavity)
  1. In the cavity a primitive, undifferntiated cell (haemocytoblast), or stem cell develops
    1. All other blood cells are derived from this precursor (multipotent stem cell)
      1. Totipotent (omnipotent) = embryonic blastocyst cells that can form ALL cells of the body and cells of the placental (not body) required for viability
      2. Pluripotent = can form ALL cells of the body only
      3. Multipotent = limited to produce ALL cells of a particular lineage (e.g. blood cells)
3. A combination of two tissues
  1. The highly vascular red marrow (50%) is the site of blood cell production
  2. The fatty yellow marrow (50%) - no blood production function
  3. The 50:50 ratio can change and is measured as the level of marrow activity (marrow cellularity)
4. Blood cell development in the marrow
  1. Immature cells are the largest and posses nucleoli (artefacts seen within the nucleus - mainly RNA in structure and are involved in mitosis)
    1. In granulated cells (WBCs - neutrophils, basophils, eosinophils) the granules are acquired later in maturation
    2. Erythrocyte nuclei are lost later in development
    3. Developing cells are retained within the marrow until they are developed sufficiently and functionally capable
      1. They are then released into the circulating bloodfor the remainder of their lifespan
Mechanism of haemopoiesis
1. Stem cells
  1. All blood cells are produced by the bone marrow
    1. They all come from a multipotent stem cell (haematopoietic stem cell, HSC)
      1. Give rise to...
        Myeloid cell lineage (RBCs, thrombocytes, granulocytes)
        Lymphoid cell lineage (lymphocytes - B and T)
      2. Self renewal / commitment into a commited cell lineage progenitor
        Commitment -> progenitor cell 1 (e.g. common lyphoid progenitor)
        Colony forming unit (CFU)
        Division and differentiation
        Morphologically distinct intermediate blast cell
        Maturation
        Mature blood cell type B
        Morphologically distinct intermediate blast cell
        Maturation
        Mature blood cell type A
        Renewed HSC (stem cell renewal)
        ->
        Commitment -> progenitor cell 2 (e.g. comon myeloid progenitor)
        Production of lineage blood cells
    2. The bone marrow and spleen form a supportive environment (called the haemopoietic microenvironment)
  2. Pluripotent stem cell (from developing blastocyst)
    1. Multipotent stem cell (HSC in bone marrow)
      1. Diameter 18-23um (large)
      2. Give rise to myeloid and lymphoid progenitors
        (Common) Myeloid progenitor
        RBCs, granulocytes (PMNs, eosinophils, basophils) and thrombocytes
        (Common) lymphoid progenitor
        Lymphocytes only
        Progenitor cells
        = irreversibly commited stem cell (cannot self-renew)
        Regulated by certain hormones or substances so that they can proliferate and undergo maturation
2. Growth factors (GFs)
  1. Haemopoiesis occurs in a suitable microenvironment provided by a stromal matrix on which stem cells grow and divide
    1. There are probably specific recognition and adhesion sites sites
      1. Extracellular glycoproteins and other compounds are involved in the binding
    2. Microenvironment (adhesion and growth factors) provided by local macrophages, ECM, adipocytes, fibroblasts etc.
  2. E.g. granulocyte colony stimulating factor (G-CSF) - in the development and maturation of neutrophils (from myeloid progenitor)
    1. Stimulates proliferation of early bone marrow cells
      1. Causes direct differentiation to one or other cell type
        Stimulates cell maturation (in neutrophil single nucleus beomces lobed; normal = 3-5 lobes)
        Supress apoptosis or affect the function of mature non-dividing cells
    2. Binds to cells expressing the correct receptor
      1. Signalling via ...
        JAK/STAT
        JAK/Ras -> myc/fos pathway
        JAK/PI3K -> Akt (blocks apoptosis)
3. Regulators
  1. Important in the differentiation of colony forming unit lineages
    1. Burst promoting activity
      1. (Erythroid) BFU-E cell line
    2. Erythropoietin
      1. (Erythroid) CFU-E cell line
      2. A glycoprotein hormone (produced in the kidneys) - stimulates the production of RBCs by stem cells i bone marrow
        Secretion is stimulated in response to low O2 (by the juxtaglomerular O2 sensor)
        Secreted to balance RBC production with RBC loss
    3. Colony stimulating factor (CSF)
      1. (Granulocyte-monocyte) CFU-GM cell line
    4. Megakaryocytic stimulating activity
      1. (Megakaryocytes) CFU-M cell line
    5. Thrombopoietin
      1. Megakaryocytes
      2. (TPO) - the major cytokine (glycoprotein hormone) that determines the proliferation of megakaryocytes (produce platelets)
        Produced in liver and kidneys
Blood cell development
1. Primitive stem cell (haemacytoblast)
  1. Erythrocyte series
    1. Erythrocyte development
      1. HSC
        Common myeloid progenitor
        Burst promoting activity
        +
        BFU-E
        CFU-E
        Rubriblast (proerythroblast)
        First identifiable RBC precursor
        Prorubricyte
        Rubricyte (normoblast)
        Looks like a monocyte - but much smaller
        Metarubricyte (loses nucleus at this stage)
        Reticulocyte (aka diffusely basophilic erythrocyte)
        Erythrocyte (mature red cell)
        Erythropoietin (EPO)
        +
  2. Leukocyte series
  3. Thrombocyte series
Different blood cell types
1. Erythrocytes
  1. Biconcave disc
  2. Approximately 7um in diameter
  3. Non-nucleated
  4. Contains haemoglobin (Hb)
  5. Major function is O2/CO2 transport
2. Leukocytes
  1. Granulocytes (Myeloid)
    1. Neutrophils
      1. 12-15um diameter
      2. characterised by segemented nucleus (2-5 lobes = normal)
      3. Dense chromatin with regions of parachromatin (lighter areas) = lobes and nodes
      4. Slightly eosinophilic (pinky) cytoplasm
      5. Important in inflammatory processes (phagocytes and mediators)
    2. Eosinophils
      1. Most readily reconisable - due to orange granules
      2. 12-15um diameter
      3. 2-3 lobes to nucleus
      4. Normally represent 0-6% of WBCs in blood
      5. Granules contain; major basic protein (MBP) - toxic to parasites
    3. Basophil
      1. Contain purple/black large granules (may obscure the nucelus)
      2. 2-3 lobes to nucleus
      3. 12-15um diameter
      4. Contain; heparin and large amaounts of histamine (involved in hypersensitivity reactions - mediated inflammation to antigen responses)
    4. Monocyes
      1. Largest cells in peripheral blood (12-20um)
      2. Abundant blue/grey (sometimes pinky) cytoplasm, with small granules
      3. Fine reddist granules may be seen
      4. Phagocytes - frequently contain vacuoles
      5. Can migrate into tissues (where they are called macrophages)
      6. Central role in the inflammatroy process - replace neutrophils during chronic inflammation
  2. Lymphocytes (Lymphoid)
    1. Vary in size (7-20um) and nuclear:cytoplasmic ratio
      1. Small lymphocytes (7-12um) have rounded nucleus with dense chromatin and little cytoplasm
      2. Can appear much larger (15-20um) with more cytoplasm and irregularly-round nucleus
    2. Represent 15-60% of peripheral blood
Bone marrow sampling and analysis
1. Myeloid:erythroid (ME) cell ratios
  1. Provides information on the relative numbers of WBCs, RBCs and their precursors
  2. In a healthy adult the number of WBC precursors exceeds the number of RBC precursors by 3 or 4 to 1
    1. This ratio changes in disease (increased in infection, dominated by myelocytes and other WBC precursors in leukaemia)
2. Cytochemistry, flow cytometry, electronic resistance and lightscattering
  1. Cytochemistry - chemical stains that react with cytoplasmic components and define different cells in blood and bone marrow
    1. Blood cells contain multiple enzymes, fats and other substances that can be detected (important in the diagnosis of myelocytic leukaemias)
      1. FAB( french-american-british) classification of acute leukaemias is based on morphology and cytochemistry
    2. Most important cytochemical studies in the study of acute leukaemia are
      1. Myeloperoxidase (MPO)
        Lysosomal enzyme in myelocytes
        Staining can reveal acute leukaemias (of myeloid lineage)
      2. Non-specific esterase
      3. Acid phosphatase (AP)
        Stains lysosomal acid phosphatase - can detect hair cell leukaemia
      4. Periodic acid schiff (PAS) stain
        Stains polysaccharides (e.g. glycogen)
  2. Flow cytometry - allows identification of blood cells according to different molecules on the cells
  3. Electronic resistance
    1. Cells pass through aperture with electric current across it (changes in current due to differernt cell sizes detected) - automated counting
  4. Light scattering
    1. Cells counted as they pass through a focused laser
      1. Results sum of
        Diffraction - bending of light around corners
        Refraction - bending due to change in speed
        Reflection - light rays reflected back by obstructive structures

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Haemopoiesis

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	Created by maisie_oj almost 11 years ago