Hematopoiesis

• Hematopoiesis

  production of blood cells and platelets

  -ocuurs in the bone marrow.

  • hematopoietic stem cells
• Sites of hematopoesis

  • fetus; 0-2months( yolk sac), 2-5months( liver&spleen) , rest bone marrow
  • infants; bone marrow of almost all bones
  • adults; flat bones, proximal ends of femur & humerus
• It depends on;

  • hematopoietic progenitor cells
  • bone marrow stroma
  • hematopoietic growth factors
• Hematopoietic prgenitor cells

  Divide into myeloid and lymphoid precursors.

  • CFU( colony forming unit)- earliest myeloid precursors that give rise to GEMM( granulocytes, erythrocytes, monocytes and megakaryocytes)
  • bone marrow- lymphoid precursors.
  • precursor cells are capable of responding to hematopoietic growth factors with increased production of other cell lines.
• Bone marrow stroma

  composed of stromal cells and a microvascular network to form an extracellular matrix.

  • stromal cells; adipocytes-collagen, fibroblasts-hemonectin, endothelial cells-proteoglycans, macrophages-fibronectin.
• Hemopoietic GFs

  regulate the proliferation and differentiation of hematopoietic stem cells and function of mature blood cells.

  • act locally via cell-to-cell contact or circulate the plasma.
  • bnd to the ECM forming niches to which stem and progenitor cells adhere.
  • prevents apoptosis
• Summary

  Medullary hematopoiesis, extramedullary is outside the bone marrow e.g liver and spleen when the bone marrow can't produce enough blood cells- this can lead to hepatoplenomegaly

  
• Erythropoiesis

  production of rbcs stimulated by erythropoietin( produced by the liver in feus and kidney in adulthood).

  production of platelets is stimulated by thrombopoietin( kidneys and liver)-form megakaryocytes via a negative feedback i.e, reduced platelets elevate their production and vice versa.
• Myeloid pathway

  Myeloid progenitor->Proerythroblast ( by erythropoietin secreted by the kidneys)->basophilic erythroblast->polychromatophilic erythroblast->orhtochromatophilic erythroblast->reticulocyte-> erythrocyte.
• Myeloid pathway 2

  by the orthochromatophilic stage; Hb production is increasing, nuclear condensation takes place and organelles start to shrink.
• Regulation of erythropoiesis

  1.RBC numbers are kept with narrow limits because an increase would impair blood flow.

  2.Tissue hypoxia leads to increased erythropoietin secretion

  3.Folic acid/B12; lack leads to failure of nuclear maturation, condensation and cell diffision leading to formation of macrocytes.

  4.IF aids in B12 absorption so impaired secretion would lead to impaired B12 absorption hence leading to pernicious anemia
• Haemopoiesis


  The process of blood cell formation
• Bone marrow


  • Has an enormous production capacity, estimated 10 billion erythrocytes and 100-900 million leukocytes produced per hour in the steady state
  • Cell numbers can be greatly amplified on demand
• Haemopoiesis


  1. Occurs in the yolk sac in the first few weeks of gestation

  2. Definitive haemopoiesis derives from stem cells in the AGM (aorta-gonads-mesonephros) region

  3. Liver and spleen are major haemopoietic organs from 6 weeks to 6-7 months of fetal life

  4. Bone marrow is the most important site from 6-7 months of fetal life onwards
• Sites of haemopoiesis


  • Yolk sac (0-2 months)
  • Liver and spleen (2-7 months)
  • Bone marrow (5-9 months and onwards)
• Medullary haemopoiesis


  Haemopoiesis in the bone marrow
• Extramedullary haemopoiesis


  Haemopoiesis in areas other than the bone marrow, e.g. fetal hematopoietic tissue like liver and spleen
• Extramedullary haemopoiesis may occur in adults when the bone marrow cannot meet physiologic needs, leading to hepatomegaly and/or splenomegaly
• Hematopoietic tissue


  Tissues involved in the proliferation, maturation, and destruction of blood cells
• 3 important components of haemopoiesis

  • Haemopoietic progenitor cells
  • Bone marrow stroma
  • Haemopoietic growth factors
• Haemopoietic stem cell


  • Rare, perhaps 1 in every 20 million nucleated cells in bone marrow
  • CD34+ CD38- and has the appearance of a small or medium-sized lymphocyte
• Cell differentiation


  Occurs from the stem cell via committed haemopoietic progenitors which are restricted in their developmental potential
• Haemopoietic progenitor cells


  • CFU-GEMM (mixed myeloid precursor)
  • CFUE (erythroid progenitors)
  • CFU-GM (granulocyte monocyte progenitor)
  • CFU-Meg (megakaryocyte progenitor)
  • Lymphoid stem cell
• Stem cell


  • Has the capability for self-renewal so marrow cellularity remains constant
  • One stem cell can produce about 1 million mature blood cells after 20 cell divisions
  • Precursor cells can respond to growth factors with increased production of one or other cell line when needed
• Bone marrow stroma


  • Forms a suitable environment for stem cell survival, growth and development
  • Composed of stromal cells (adipocytes, fibroblasts, endothelial cells, macrophages) and a microvascular network
  • Stromal cells secrete extracellular molecules and growth factors necessary for stem cell survival
• Mesenchymal stem cells


  Thought to be critical in stromal cell formation
• Components of bone marrow stroma

  • Stromal cells (adipocytes, fibroblasts, endothelial cells, macrophages)
  • Extracellular matrix (fibronectin, laminin, collagen, proteoglycans)
• Haemopoietic growth factors


  Glycoprotein hormones that regulate the proliferation and differentiation of haemopoietic progenitor cells and the function of mature blood cells
• Haemopoietic growth factors


  • May act locally or circulate in plasma
  • Bind to extracellular matrix to form niches for stem and progenitor cells
  • Can cause cell proliferation, differentiation, maturation, prevent apoptosis, and affect function of mature cells
  • Stromal cells are the major source except for erythropoietin and thrombopoietin
  • Two or more factors may synergize in stimulating a cell
  • One factor can stimulate production of another factor or receptor
• Haemopoietic growth factors


  • SCF, Flt-L (act on pluripotential stem cells)
  • IL-3, GM-CSF, IL-6, G-CSF, Thrombopoietin (act on multipotential progenitor cells)
  • G-CSF, M-CSF, IL-5, Erythropoietin, Thrombopoietin (act on committed progenitor cells)
• Myeloid and lymphoid growth factors

  • Glycoproteins that act at very low concentrations
  • Act hierarchically
  • Usually produced by many cell types
  • Usually affect more than one lineage
  • Usually active on stem/progenitor cells and on functional end cells
  • Usually show synergistic or additive interactions with other growth factors
  • Often act on the neoplastic equivalent of a normal cell
  • Multiple actions: proliferation, differentiation, maturation, functional activation, prevention of apoptosis of progenitor cells
• Haemopoietic growth factors


  • IL-1
  • TNF
  • SCF
  • Flt-L
  • IL-3
  • GM-CSF
  • IL-6
  • G-CSF
  • Thrombopoietin
  • G-CSF
  • M-CSF
  • IL-5 (eosinophil-CSF)
  • Erythropoietin
  • Thrombopoietin
• Later acting factors


  Erythropoietin, G-CSF, M-CSF, IL-5 and thrombopoietin act to increase production of one or other cell lineage in response to the body's need
• Infection or inflammation


  Releases IL-1 and tumour necrosis factor (TNF) which then stimulate stromal cells to produce growth factors in an interacting network
• Cytokines such as transforming growth factor-ẞ (TGF-B) and y-interferon (IFN-y)


  Can exert a negative effect on haemopoiesis and may have a role in the development of aplastic anaemia
• Erythroid burst-forming unit (BFU-E)


  The most primitive single lineage committed erythroid progenitor in humans
• Erythropoiesis


  1. In response to the combination of EPO and one of SF, IL-3, or GM-CSF, the progeny of the first few cellular divisions are motile and form subpopulations of erythroid colony-forming units (CFU-E)

  2. Each of these units subsequently forms a large colony of proerythroblasts, which become more mature erythroblasts and a few enucleated reticulocytes
• Proerythroblasts


  The earliest recognizable forms
• Erythropoiesis


  1. Proerythroblasts divide and mature through basophilic, polychromatic, and orthochromatic normoblast cells to form the reticulocyte

  2. This process involves a reduction in cell size, nuclear condensation and extrusion, and hemoglobin accumulation

  3. On average, each proerythroblast can form approximately eight reticulocytes
• Erythropoietin


  • Essential for the terminal maturation of erythroid cells
  • Its major effect appears to be at the level of the CFU-E during adult erythropoiesis; recombinant preparations are as effective as the natural hormone
  • CFU-E do not survive in vitro in the absence of EPO. Since the majority of CFU-E are cycling, their survival in the presence of EPO may be tightly linked to their proliferation and differentiation to mature erythrocytes