Hematopoietic Growth Factors

• Haematopoiesis: Formation of blood cells from the

hematopoietic stem cells

• Haematopoietic stem cells: Define

• Haematopoietic growth factors (HGFs): Small, secreted

extracellular glycoproteins that bind to receptors on the
surface of hematopoietic cells

• Required for the survival, proliferation and differentiation

of hematopoietic progenitors and regulation of the
functional activation of specific cells with which they
interact
 Hematopoietic Growth Factors
• Granulocyte colony stimulating factor (G-CSF)
• Macrophage colony stimulating factor (M-CSF)
• Granulocyte-macrophage colony stimulating factor
(GM-CSF)
• Erythropoietin (EPO)
• Interleukin-3 (IL-3)
• Thrombopoietin (TPO)
• Interleukin-5 (IL-5)
• Stem cell factor (SCF)
• Interleukin-11 (IL-11)
 Haematopoietic Growth Factors
Pluripotent/totipotent/multipotent stem cell

IL-11?
 Haematopoiesis
• Blood-cell development progresses from a haematopoietic
stem cell (HSC), which can undergo either self-renewal or
differentiation into a multilineage committed progenitor
cell: a common lymphoid progenitor (CLP) or a common
myeloid progenitor (CMP).
• These cells then give rise to more-differentiated progenitors,
comprising those committed to two lineages that include T
cells and natural killer cells (TNKs), granulocytes and
macrophages (GMs), and megakaryocytes and erythroid
cells (MEPs)
• Ultimately, these cells give rise to unilineage committed
progenitors for B cells (BCPs), NK cells (NKPs), T cells
(TCPs), granulocytes (GPs), monocytes (MPs), erythrocytes
(EPs), and megakaryocytes (MkPs)
 Haematopoietic Growth Factors
• Cytokines and growth factors that support the survival,
proliferation, or differentiation of each type of cell are
shown in red
• For simplicity, the three types of granulocyte progenitor
cells are not shown; in reality, distinct progenitors of
neutrophils, eosinophils, and basophils or mast cells exist
and are supported by distinct transcription factors and
cytokines
• Examples: Interleukin-5 (IL-5) in the case of eosinophils,
stem-cell factor [SCF] in the case of basophils or mast cells,
and G-CSF in the case of neutrophils).
• IL denotes interleukin, TPO thrombopoietin, M-CSF
macrophage colony-stimulating factor, GM-CSF
granulocyte-macrophage CSF,and EPO erythropoietin
 Haematopoietic Growth Factors
• Outline the roles of the following during haematopoiesis:
• G-CSF
• M-CSF
• GM-CSF
• EPO
• IL-3
• TPO
• IL-5
• SCF
• IL-11
• Other IL excluding IL-3 and IL-5 are only considered
cytokines: Involved mainly in immune response
Production of Haematopoietic Growth Factors
 Production of Haematopoietic Growth Factors

• Production of growth factors: Constitutive and inducible

and subject to adsorption by receptor-bearing cells

• Erythropoietin (red arrows) is inducible by hypoxia in the

kidney and constitutive in the liver (10 percent of total body
erythropoietin), and it is excreted in the urine

• G-CSF (green arrows) is mostly inducible in tissues from

fibroblasts and macrophages and from endothelial cells by
inflammatory mediators (interleukin-1, interleukin-6, and
tumor necrosis factor α
 Production of Haematopoietic Growth Factors
• Thrombopoietin (blue arrows) is produced constitutively by
the liver (accounting for approximately 50 percent of baseline
thrombopoietin levels) and kidney (accounting for a minority
of the total amount) and is inducible in the liver by
inflammatory mediators (especially interleukin-6) and from
bone marrow stromal cells by thrombocytopenia

• In addition, both G-CSF and thrombopoietin are removed

from the circulation by receptor-mediated uptake and
destruction by the mature cells that bear the corresponding
receptors on neutrophils and platelets

• Arrows indicate the production and secretion of

haematopoietic growth factors
Regulation of Production and Cellular Sources of
Colony Stimulating Growth Factors
Cellular Sources of Haematopoietic Growth Factors

Haematopoietic Growth Factor Cellular source

IL-3 T lymphocytes

GM-CSF T lymphocytes, monocytes and fibroblasts

G-CSF Monocytes, fibroblasts and endothelial cells

M-CSF Monocytes, fibroblasts and endothelial cells

Erythropoietin Peritubular cells of the kidney, Kupffer cells

 Haematopoietic Growth Factors in Clinical Use
• Growth factors are produced by recombinant DNA technology
• Define “recombinant DNA technology”

Are these: neutropenia, thrombocytopenia, … new terms?

 G-CSF
• Acts primarily on the neutrophil component of the blood
• Avariety of mechanisms of action, including stimulation of
granulocyte colonies, differentiation of progenitor cells
toward neutrophil lineage, and stimulation of neutrophil
maturation
• Overall, it increases the number of neutrophils capable of
fighting bacteria

• Clinically indicated for use in:

■ Chemotherapy-induced neutropenia
■ Collection of stem cells for transplantation
■ Bone marrow or peripheral stem cell transplantation
■ Congenital neutropenia
 GM-CSF
• GM-CSF exerts its effect via stimulation of colonies
containing neutrophils, eosinophils and monocytes

• Clinical setting: Effects of GM-CSF include increasing the

number of neutrophils, eosinophils, and monocytes and
improving the function of mature neutrophils, eosinophils
and monocytes

• Approved for use in:

■ Chemotherapy-induced neutropenia
■ Bone marrow or peripheral stem cell transplantation
■ Collection of stem cells for transplantation
 Erythropoietin
• Stimulates stem cells toward the production of RBCs

• Prior to initiating therapy, adequate iron stores are required

to sustain the increased hemoglobin production

• Erythropoietin is indicated for treating patients with anemia

resulting from a variety of causes such as:
■ Chronic renal failure (with or without dialysis)
■ AIDS
■ Chemotherapy
■ Neonatal anemia due to prematurity
■ Rheumatoid arthritis
 Oprelvekin

• Oprelvekin is recombinant human interleukin-11

• Stimulates megakaryocytic progenitor stem cells and

maturation of megakaryocytes with the eventual result of
increasing platelet production

• Oprelvekin is indicated for:

■ Prevention of severe thrombocytopenia
■ Reduction of the need for platelet transfusions after
standard chemotherapy