Hematopoiesis Stem Cell Differentiation

Hematopoiesis

• A multipotent stem cell differentiates into either a common lymphoid progenitor cell or a common myeloid progenitor cell
• The types and amounts of growth factors in the microenvironment of a stem cell or progenitor cell control its differentiation
• During lymphoid and myeloid lineage development, stem cells differentiate into progenitor cells, which lose self-renewal capacity and commit to a particular cell lineage

Stromal Cells and the Microenvironment

• In bone marrow, HSCs grow and mature on a meshwork of stromal cells, which are nonhematopoietic cells that support HSC growth and differentiation
• Stromal cells include fat cells, endothelial cells, fibroblasts, and macrophages
• Stromal cells influence HSC differentiation by providing a hematopoietic-inducing microenvironment (HIM) consisting of a cellular matrix and growth factors

Hematopoietic Growth Factors

• Hematopoietic growth factors are soluble agents that arrive at target cells by diffusion or membrane-bound molecules on stromal cells that require cell-to-cell contact
• During infection, hematopoiesis is stimulated by the production of hematopoietic growth factors by activated macrophages and T cells

Hematopoiesis Regulation

• Hematopoiesis is regulated at the genetic level
• The development of pluripotent HSCs into different cell types requires the expression of different sets of lineage-determining and lineage-specific genes at appropriate times and in the correct order
• Transcription factors such as GATA2 and Ikaros play important roles in hematopoiesis

Hematopoietic Homeostasis

• Steady-state regulation of hematopoiesis is accomplished through various mechanisms, including:
  • Control of cytokine levels and types produced by bone marrow stromal cells
  • Production of cytokines with hematopoietic activity by other cell types, such as activated T cells and macrophages
  • Regulation of receptor expression for hematopoietically active cytokines in stem cells and progenitor cells
  • Removal of cells by controlled induction of cell death

Programmed Cell Death (Apoptosis)

• Apoptosis is an induced and ordered process in which cells actively participate in bringing about their own demise
• Morphologic changes in apoptosis include:
  • Decreased cell volume
  • Modification of the cytoskeleton resulting in membrane blebbing
  • Condensation of chromatin
  • Degradation of DNA into smaller fragments
• Apoptotic cells are phagocytosed by macrophages, preventing inflammation

Leukocytes

• White blood cells that provide either innate or specific adaptive immunity
• Myeloid cells: first line of defense, non-specific innate immunity
  • Neutrophils
  • Eosinophils
  • Basophils/Mast cells
  • Monocytes/Macrophages/Dendritic cells
• Lymphoid cells:
  • Non-specific immunity
    • Natural Killer cells
  • Humoral and Cell-Mediated specific immunity
    • B Lymphocytes
    • T Lymphocytes (Helper and Cytolytic)

Neutrophils

• Produced in the bone marrow from myeloblast-type stem cells
• Main role is in inflammation
• First cells to arrive at the site of inflammation by leaving the blood vessels (extravasation)
• Attracted by chemotactic factors, including complement proteins, clotting proteins, and T cell-derived cytokines

Eosinophils

• Granulocytes that stain intensely with 'eosin'
• Bilobed nucleus
• Contain basic crystal granules in cytoplasm that mediate toxic reactions to large parasites
• Involved in asthma and parasitic infections

Basophils

• Found in low numbers in the blood
• Act like mast cells
• Involved in Type I hypersensitivity responses
• Have high-affinity Fc receptors for IgE on their surface

Lymphoid Leukocytes

• B cells, T cells, and natural killer cells
• B and T lymphocytes that have not interacted with antigen are referred to as naive or unprimed
• Interaction with antigen induces cells to enter the cell cycle and differentiate into effector cells or memory cells

B Lymphocytes

• Develop from stem cells in the bone marrow
• Produce antibodies with specificity for antigens
• Plasma cells are activated B cells
• Upon activation, a B cell can switch to produce a different class of antibody with the same antigen specificity

T Lymphocytes

• Regulate immune responses
• Integral in cell-mediated immunity
• Critical in B cell-antibody production
• Mature T cells display either CD4 or CD8
• Develop in the thymus
• Cells with a CD4 marker are called helper T cells (Th cells)
• Cells with a CD8 marker are cytotoxic T cells (Tc cells)
• Each T cell has a TCR to recognize antigen

Surface Molecules of T Lymphocytes

• TCR, T cell receptor
• CD3, TCR signaling complex
• Thy-1, mouse T cell marker
• CD45RO, Leukocyte common antigen for memory T cells
• CD45RA, Leukocyte common antigen for naive T cells
• CD2, LFA-3 adhesion molecule
• CD28, co-stimulatory molecule that binds B7
• CD5, co-stimulatory molecule
• CD7, signal transduction