Hematopoiesis

Chapter 4: Hematopoiesis

Introduction to Hematopoiesis

  • Hematopoiesis is defined as the process of blood cell production, differentiation, and development.
  • The hematopoietic system includes:
    • Bone Marrow
    • Liver
    • Spleen
    • Lymph Nodes
    • Thymus (in developing adults)
  • Fetal hematopoiesis occurs in several locations:
    • Yolk Sac
    • Aorta-gonad-mesonephros (AGM) Region
    • Fetal Liver
    • Bone Marrow

Origin of Blood Cells

  • There are three types of stem cells:
    • Totipotential Stem Cells:
    • Present in the first few hours post-fertilization.
    • Most versatile, can develop into any human cell type and support development from embryo to fetus.
    • Pluripotential Stem Cells:
    • Present several days after fertilization.
    • Can develop into any cell type, but cannot develop into a fetus.
    • Multipotential Stem Cells:
    • Derived from pluripotential stem cells.
    • Found in adults, limited to specific types for tissue formation.
    • Example: Bone marrow stem cells can produce all types of blood cells, as well as bone, cartilage, and adipose cells.

Phases of Hematopoiesis

1. The Embryonic Phase
  • Occurs in the yolk sac within blood islands.
  • Begins approximately on day 19 post-conception and continues until the 8th week of gestation.
  • Cells produced during this phase include:
    • Erythrocytes
    • Macrophages
    • Platelets
  • Erythrocytes contain Gower and Portland hemoglobin.
2. The Fetal Hepatic Phase
  • Begins at 5 to 7 weeks post-conception and lasts until approximately 24 weeks of gestation (6th month).
  • Peak hematopoiesis occurs at around the 3rd month of gestation.
  • Clusters of the following cells colonize the fetal liver:
    • Erythroblasts
    • Granulocytes
    • Monocytes
  • A microenvironment conducive to hematopoiesis is created by various cell populations producing cytokines and chemoattractants to the liver.
  • Other organs such as the spleen, thymus, and lymph nodes also contribute to hematopoiesis during this phase.
3. The Medullary (or Myeloid) Phase
  • The bone marrow becomes large enough to have marrow cavities by the fifth month of gestation.
  • The bone marrow assumes its role as the chief organ of hematopoiesis in adults, with the liver and spleen acting as supplementary organs for hematopoiesis when needed (this process is termed extramedullary hematopoiesis).
  • Important factors present during this phase include:
    • Erythropoietin (EPO)
    • Granulocyte Colony-Stimulating Factor (G-CSF)
    • Granulocyte-Monocyte Colony-Stimulating Factor (GM-CSF)
  • The myeloid to erythroid (M:E) ratio is 3:1 at this stage.

Developmental Anatomy of Blood Cells

  • The anatomical sites of blood cell development vary through different life stages:
    • Prenatal Hemopoiesis:
    • Occurs in diverse sites such as the yolk sac, liver, bone marrow.
    • Postnatal Hemopoiesis:
    • Primarily occurs in the bone marrow, with varying cellularity at different ages.
Bone Marrow Sites and Their Functions
  • Bone marrow is critically involved in the production and maturation of various blood cell types, with different functional sites within the marrow fulfilling specialized roles.
Cellular Elements of Bone Marrow
  • Phases of Hematopoietic Cells:
    • Primitive, Multipotential Cells:
    • The most immature group with capabilities for self-renewal and differentiation into all blood cell lines.
    • Intermediate Cells (Committed Progenitors):
    • Committed to developing into distinct blood cell lines.
    • Precursors:
    • Morphologically distinguishable cells giving rise to mature cells.
    • Mature Cells:
    • Fully developed blood cells with specific physiological functions.
Hematopoietic Progenitor Cells (HPCs)

  • Erythropoiesis:

    • Occurs in specialized anatomical sites known as erythropoietic islands, which are niches for erythroid precursors to proliferate, differentiate, and enucleate.
    • Each island consists of an iron-laden macrophage surrounded by erythroblasts, where cell-cell and cell-extracellular matrix interactions occur, along with central macrophage functions.

  • Granulopoiesis:

    • Approximately 23% to 85% of nucleated cells in normal bone marrow are myeloid cells.
    • Development stages in granulopoiesis occur in certain pools:
    • Early myeloid cells are located in cords and around bone trabeculae.
    • Neutrophils mature in a proliferating pool over 3 to 6 days and can enter peripheral circulation with a lifespan of 6 to 10 hours.

  • Lymphopoiesis:

    • Lymphocytes and plasma cells are produced in lymphoid follicles, with plasma cells typically located along the vascular wall.
    • Lymphoid cells generally constitute 1% to 5% of nucleated cells in the marrow.

  • Megakaryopoiesis:

    • Occurs adjacent to the sinus endothelium where megakaryocytes produce platelets by extending cytoplasmic processes through the vascular wall, taking about 5 days to develop.
Other Bone Marrow Cells
  • Marrow Stromal Cells:
    • Composed of various cells including reticulum cells, histiocytes, adipocytes, and endothelial cells.
  • Mast Cells:
    • Origin from mesenchymal cells, typically found in bone marrow.
  • Macrophages:
    • Large cells in the bone marrow, also known as reticulum or histiocytes.
  • Osteoblasts:
    • Bone matrix synthesizing cells resembling plasma cells, observed typically in groups.

Interleukins

  • Interleukins are protein molecules that aid in the proliferation and differentiation of blood cell lines in conjunction with hematopoietic growth factors. They are a type of cytokine acting as cell signaling molecules within the cytokine superfamily.
  • Functions of interleukins include:
    • Stimulation of hematopoietic growth.
    • Serving as primary messengers and directors of the immune system.
    • A known total of 35 interleukins are characterized, with more expected to be discovered.

Cytokines

  • Definition:
    • Proteins produced by various cell types, including interleukins, colony-stimulating factors, and interferons.
  • Functionality of cytokines involves:
    • Binding to receptors on target cells
    • Inducing intracellular signaling for survival, proliferation, or differentiation responses leading to an activated signaling pathway.
Hematopoietic Growth Factors
  • Hematopoietic growth factors are encoded by single genes located on specific chromosomes:
    • EPO on chromosome 7
    • G-CSF on chromosome 17
  • Their roles include:
    • Regulating proliferation and differentiation of hematopoietic progenitor cells (HPCs) and the survival and function of mature blood cells.
    • Laboratory synthesis of these factors is ongoing, with clinical trials underway for patients with depleting cell counts due to chemotherapy.
Examples of Hematopoietic Growth Factors
  • G-CSF and GM-CSF primarily affect myeloid cells.
  • IL-7 stimulates T and B lymphocytes.
  • IL-12 targets natural killer (NK) cells.
  • Mobilization of HPCs:
    • Hematopoietic growth factors are also capable of mobilizing HPCs into peripheral circulation.

Examination of Maturing Blood Cells

  • A comprehensive examination of the bone marrow includes smears and histological tissue sections. Morphological evaluation is crucial in recognizing maturation stages in both bone marrow and peripheral blood.
Cellular Characteristics in Cell Identification
  • Two key characteristics to observe during cell identification include:
    • Overall cell size
    • Nuclear-cytoplasmic ratio

Nuclear Characteristics

  • Important Features for Cell Identification:
    • Chromatin Pattern:
    • Lymphocytes display smooth or homogeneous chromatin until maturity, while granulocytes progress from fine to highly clumped patterns. Monocytes exhibit a lacy pattern that refines as they mature.
    • Erythrocytes develop a clumped pattern until the dense nucleus (pyknotic) is extruded.
    • Nuclear Shape:
    • Lymphocytes generally maintain a round to oval nucleus.
    • Monocytes can have kidney bean shapes.
    • Neutrophils, eosinophils, and basophils exhibit segmented nuclei with 2 to 5 lobes.
    • Presence of Nucleoli:
    • Initially present in all three cell lines but typically not visible in mature cells, indicating the synthesis of ribosomal RNA.
    • Specific counts of nucleoli in various blast cells, e.g., lymphoblasts (1-2), myeloblasts (1-5), monoblasts (1-2), erythroblasts (0-2), and megakaryoblasts (1-5).

Cytoplasmic Characteristics

  • Staining Color and Intensity:
    • Younger cells appear more blue, while mature cells transition from blue to pink.
  • Granulation:
    • The presence and type of granules can help identify specific cell types.
  • Shape of Cell Types:
    • Distinctive shapes for blasts, monocytes, and megakaryocytes.
  • Quantity of Cytoplasm:
    • In cells like megakaryocytes, cytoplasm quantity increases with maturation.
  • Vacuolization:
    • Normal in monocytes; abnormally seen in other cell types.
  • Inclusion Bodies:
    • Such as Auer rods, helpful in cell identification.

Summary Table of Mature Blood Cells in Peripheral Blood

  • A table (Table 4.5) highlights the normal adult values and selected characteristics of mature leukocytes, including:
    • Neutrophil:
    • Nuclear Shape: Segmented
    • Average Chromatin: Very clumped
    • Cytoplasmic Color: Pink with many granules (some blue)
    • Percentage: 56%
    • Band Form Neutrophil:
    • Nuclear Shape: Curved
    • Average Chromatin: Moderately clumped
    • Cytoplasmic Color: Blue/pink with many pink granules
    • Percentage: 3%
    • Lymphocyte:
    • Nuclear Shape: Round
    • Average Chromatin: Smooth
    • Cytoplasmic Color: Light blue, few granules
    • Percentage: 34%
    • Monocyte:
    • Nuclear Shape: Indented/Twisted
    • Average Chromatin: Lacy
    • Cytoplasmic Color: Gray-blue with many dusty blue granules
    • Percentage: 4%
    • Eosinophil:
    • Nuclear Shape: Lobulated
    • Average Chromatin: Very clumped
    • Cytoplasmic Color: Granulated, many orange granules
    • Percentage: 2.7%
    • Basophil:
    • Nuclear Shape: Lobulated
    • Average Chromatin: Very clumped
    • Cytoplasmic Color: Granulated, many dark blue granules
    • Percentage: 0.3%