Hematology lecture 8-9-2012

GROWTH FACTORS
Erythropoietin (Epo)
Stimulates proliferation, growth, and differentiation of erythroid precursors
Dominant effect on CFU-E, pronormoblasts and basophilic normoblasts.
Maximal BFU-E stimulates requires IL-3, GM-CSF and Epo.
Granulocyte/Macrophage Colony Stimulating factor (GM-CSF)
A pan-myeloid growth factor, stimulating erythroid, granulocyte, monocytes,
Megakaryocyte and eosinophil progenitors.
Increases neutrophils, monocytes and eosinophils and activates phagocytize
function
Monocytes/macrophage colony stimulating factor (M-CSF, CSF-1)
Stimulates monocytes-macrophage production and activity.
Induces macrophage production of IL-1.
Thrombopoietin (Tpo)
Primary regulator of platelet production
Essential for full maturation of Megakaryocyte and enhances platelet production
Interleukin 3 (IL-3)
A multipotential colony stimulating factor with activities similar to GM-CS but
occurs at an earlier level
Interleukin 5 (IL-5)
Activates cytotoxic T cells
Induces immunoglobulin secretion
Stimulates eosinophils
Interleukin 6 (IL-6)
Synergizes with IL-3 and other early acting cytokines to support the proliferation Of
early hematopoietic progenitors
Synergizes with GM-CSF and M-CSF in the formation of granulocyte and
macrophages colonies respectively.
Stimulates immature Megakaryocytes in the presence of other Megakaryocyte
growth factors.
Interleukin 11 (IL-11)
Promotes formation of antigen-specific immunoglobulin-secreting B cells.
Synergizes with IL-3 to stimulate Megakaryocyte production and pluripotential
stem cell proliferation.

Synergizes with IL-4 to promote stem cell proliferation.

Stem Cell Factor (SCF)
Synergizes with most other growth factors including GM-CSF and IL-3 to
stimulate myeloid, erythroid and lymphoid progenitors.
Stimulates growth, viability and addition of primitive progenitor cells, BFU-E,
CFU-E, CFU-GM, CFU-Meg and mast cells.
It also stimulates growth of B cells, T cells, NK cells and dendritic cells.
Flt-3 Ligand (FL)
Stimulates primitive progenitor cells often in synergy with SCF.
Acts synergistically with other growth factors to stimulate T cells, B cells, NK cells
and dendritic cells.
Leukemia inhibitory factor (LIF)
Induces proliferation of multipotential (CFU-GEMM) and eosinophil (CFU-EO)
progenitors when added with serum.
Increases the size of BFU-E.
Oncostatin M (OSM)
Th 1 stimulation of hematopoietic progenitor cell proliferation.
In vivo administration results in accumulation of immature and mature T cells in
the lymph nodes.

OTHER CYTOKINES WITH HEMATOPOIETIC ACTIVITY

Interleukin 1(IL-1)
Synergizes with multiple cytokines to induce hematopoietic colony formation.
Induces neutrophilia.
*not important for normal hematopoiesis
Interleukin 2(IL-2)
T cell growth factor
Require the presence of T Cells.
Interleukin 4 (IL-4)
T-cell derived B cell growth factor.
An intermediate-acting cytokines that acts on early hematopoietic progenitors.
Interacts with lineage-specific cytokines such as G-CSF and Epo to produce
neutrophil and erythroid colonies.

Interleukin 7 (IL-7)
A pro-B cell growth factor.
Prominent activity on immature and mature T cells.
Stimulates proliferation and prevents apoptosis of both T cell and B cell
progenitors.
Critical regulator of homeostatic proliferation and survival of naive T cells.
Interleukin 9 (IL-9)
Acts on an early progenitor population of IL-3 responsive BFU-E (Epo dependent).
Increases the number of multipotential progenitors in the presence of SCF.
Interleukin 10 (IL-10)
Modestly affects hematopoiesis by inhibiting BFU-E probably by suppressing
GM-CSF.
Also inhibits CFU-GM by the same mechanism as above.
It stimulates Megakaryocytes, mast cells and multilineage colonies.
Interleukin 12 (IL-12)
Stimulates mature T cells and NK cells.
Promotes the development of Th 1 CD4+ T cells
Requires the presence of other hematopoietic factors to enhance colony formation.
Interleukin 17 (IL-17)
Does not have a direct effect on hematopoietic progenitors but induces secretion of
IL-6, IL-8, GM-CSF, Epo and IL-1.
Interleukin 20 (IL-20)
Stimulates the hematopoietic multipotential progenitors without affecting the
more mature progenitors.
CANDIDATE STEM CELL REGULATORS
Notch Ligands
Expression in murine hematopoietic cells resulted in increase in the number of
early progenitor cells, however its effect in humans is less remarkable.
Wnt Family Members
Some Wnt proteins Re mitogenic for pro-B cells.
Wnt-3A reduces the number of B Cells and myeloid-lineage cells in bone marrow
cultures in the presence of stromal cells.

Bone Morphogenic Proteins

Promote the differentiation of human embryonic stem cells into cells belonging to
the hematopoietic lineage in combination with other cytokines.

Vascular Endothelial Growth Factor (VEGF)

VEGF-A exerts both a stimulatory effect on mature subsets of hematopoietic
progenitors and an inhibitory effect on the more immature subsets in the
presence of other cytokines.

CLASSIC GROWTH FACTORS WITH HEMATOPOIETIC ACTIVITIES

Insulin-like Growth Factors (IGF) I and II
When added to bone marrow cells, IGF-1 mediates an Epo-like activity even in the
absence of added Epo.
IGF-2 has more significance for colony formation by cord blood progenitors.
Basic Fibroblast Growth Factor (bFGF)
BFGF enhances the colony stimulating activity of IL-3 and GM-CSF on CD34+,
CD33- progenitors in vitro.
It increases the number of CFU-S9 and CFU-S12 in synergy with GM-CSF.
Hepatocyte Growth Factor (HGF)
HGF exerts wide mitogenic and morphogenic activity on multiple cell types.
It has no colony-stimulating activity when used alone, but it synergizes with GMCSF and IL-3.
INHIBITORY CHEMOKINES
Macrophage Inflammatory Protein 1 Alpha (CCL-3)
Inhibits multi-cytokine induced growth of CFU-GEMM, BFU-E and CFU-GM.
In vivo administration results in suppression of hematopoiesis.
Interferons (IFNs)
IFNs are well-known inhibitors of hematopoietic progenitors, including CFUGEMM, CFU-GM, and megakaryocytic (CFU-MK) progenitors.
Tumor Necrosis Factor Alpha (TNF alpha)
It directly inhibits hematopoietic progenitors by down-regulating CSF receptors.
It also synergizes with IFN gamma to inhibit proliferation of hematopoietic
progenitor cells.

Transforming Growth Factor Beta (TGF beta)

When combined with other cytokines, it exerts inhibitory or stimulatory functions
on hematopoietic colony formation.
It inhibits proliferation of early progenitor stem cells but not of late progenitors.

Lactoferrin and H-Ferritin

Lactoferrin has both direct and indirect inhibitory effects on progenitor cells.
H-ferritin has direct inhibitory activity on progenitor cells.