Hematopoiesis

heme precursors Hematopoiesis Overview:  Definition: the process of making blood cells. Location: in the bone marrow after birth. Production: 250 x 10^9 blood cells per day

  1. Natural Killer cells: killing of infected cellsNormal Blood Cells:
  2. Erythrocytes (RBCs): transport O2 and CO2
  3. Leukocytes (WBCs)
  4. Granulocytes
    1. Neutrophils
    2. Eosinophils
    3. Basophils
  5. Agranulocytes
    1. Lymphocytes
      1. B-cells-Ig: humoral immunity
      2. T-cells-cytokines: cellular immunity
  1. Monocytes
  2. Platelets (come from Megakaryocytes)
  3. Time Course:

1st Trimester: Yolk Sac mesodermà 2nd Trimester: Liver and Spleenà 3rd Trimester: Bone Marrow

Hematopoiesis: The Process

  1. Hemopoietic Stem Cells (HSCs)
  2. Pluripotent: capable of asymmetric division and self-renewal
  3. Daughter cells form specific, undifferentiated cell types or remain stem cells
  4. HSCs à Lymphoid Stem Cells or Myeloid Stem Cells
  5. Lymphoid Stem Cells give rise to:
  6. Lymphopoiesis à B- cells and T-cells
  7. Myeloid Stem Cells give rise to:
  8. Erythropoiesis à RBCs
  9. Megakaryocytopoiesis à Platelets

iii. Granulopoiesis à Neutrophils, Eosinophils, Basophils

  1. Monopoiesis à Monocytes
  2. Hematopoesis Environment:
  3. Bone Marrow (adult)
  4. Red: contains blood and hemopoietic cells
  5. Stroma: contains reticular cells (secrete colony-stimulating factors), reticular fibers (support hemopoietic cells and macrophages)
  6. Matrix: collagen type I, proteoglycans, fibronectin, laminin

iii. hemopoietic cords or islands of hemopietic cells (C)

  1. Sinusoidal capillaries (S)
  2. Nutrients: vitamins, iron; Cytokines: growth factors, interleukins, TNF
  3. Yellow: contains adipocytes (A)
  1. Erythropoiesis
  2. Proerythroblast à Erythrocyte in 7 days, Lasts 120 days
  3. 4 mitotic divisions
  4. Increase in hemoglobin concentration
  5. Increase in chromatin condensation and extrusion of pyknotic nucleus
  1. Driven by Erythropoietin (EPO) produced by kidneys:
  2. Stimulates production of mRNA for globin: protein component of hemoglobin
  3. Granulopoiesis
  4. Myeloblast à Neutrophil, Eosinophil, or Basophil in 10-14 days,

Lasts 6-7 hours in circulation, up to 4 days in tissue

  1. 3 mitotic divisions
  2. Synthesis of proteins for azurophilic andspecific granules
  1. Regulated by GM-CSF, G-CSF, M-CSF, IL-5
  2. Megakaryocytopoiesis
  3. Megakaryoblast à Platelet in 10 days, Lasts for 10 days
  4. 3-5 endomitotic divisions (DNA replication not separated by division = polyploidy)
  5. Driven by thrombopioetin in liver
  6. Monopoiesis
  7. Monoblast à monocyte
  8. 2 divisions
  9. Primary lysosomes (observed as azurophilic granules in blood monocytes) develop
  10. Mature monocytes enter blood stream to circulate for about 8 hours
  11. Later enter tissues where mature into Macrophages and function for several months
  12. Lymphopoiesis
  13. Lymphocyte progenitor cells originate in bone marrow
  14. Some migrate to thymus to form T lymphocytes
  15. Others stay in bone marrow to form B lymphocytes
  16. Both migrate to populate specific regions of peripheral lymphoid organs

Regulation

  1. Common Production Pathway

Growth Factors and Interleukins à

Hematopoietic Stem Cells, Progenitor Cells, or Precursor Cells à

Signal Transduction ->

Transcription factors ->

Gene Expression ->

Blood Cell Formation

  1. White Blood Count

Presentation in Normal Infection

  1. Neutrophils:
    1. Phagocytic, rapid response.
    2. May be high in bacterial infection, acute viral infection, inflammation, and stress.
  2. Lymphocytes:
    1. B-cells, T-cells, and natural killer cells
    2. May be high in viral infections
    3. Both immediate and delayed role for infection or inflammation
  3. Monocytes:
    1. Differentiate into macrophages
    2. High in viral or fungal infections, chronic diseases
    3. Respond to inflammation, infection, and foreign bodies by ingesting and digesting foreign material
  4. Eosinophils:
    1. Can combat inflammation during allergic reactions and parasitic worms
    2. High in these instances
    3. Phagocytize antigen-antibody complexes
  5. Basophils:
    1. Release substances to enhance inflammatory reactions, much like mast cells
    2. Elevated in allergic reactions, hypothyroidism.
    3. Contain heparin, which keeps blood from clotting too quickly.
  6. Reticulocyte:
    1. Immature red blood cells, still contain cytoplasmic RNA
    2. Measures how rapidly reticulocytes are produced by the bone marrow and released into the blood stream
    3. Increased in hemolytic anemia, blood loss (before development of iron deficiency), B12 or folate deficiency or drug-induced anemia
    4. Decreased in Iron deficiency anemia, aplastic anemia, anemia of chronic disease, megaloblastic anemia, bone marrow suppression or infiltration
  7. Bands:
    1. Immature neutrophil
    2. Elevations occur when these premature cells are released from storage compartment in marrow due to bacterial infection, or problem with regulation of hematopoiesis (acute or chronic myeloproliferative disorder) such as myeloid leukemia, idiopathic myelofibrosis, other acute leukemias
  8. Metamyelocytes:
    1. Neutrophil, Eosinophil, or Basophil precursor
    2. Seen during infections, pregnancy, leukemoid reactions, recovery from myelosuppression
  9. Myelocytes:
    1. Neutrophil, Eosinophil, or Basophil precursor
    2. Seen during infections, pregnancy, leukemoid reactions, recovery from myelosuppression
  10. Promyelocytes
    1. Neutrophil, Eosinophil, or Basophil precursor
    2. Increase during hematologic malignancies, bone marrow invasion, fibrosis
  11. Blasts (e.g. lymphoblasts, myeloblasts):
    1. Most immature recognizable cell that has morphologically began to differentiate in each “poiesis” series.
    2. Never normal to see blasts on peripheral smear; need hematologic consultation, bone marrow examination, underlying malignant hematologic disorder