Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

II. Hematopoiesis
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progenitor cell is believed to give rise to all nonlymphoid
blood cells, as well as macrophages, myeloid dendritic
cells, osteoclasts, and mast cells ( Kaushansky, 2006a ).
HPCs proliferate with higher frequency than do HSCs, but
the self-renewal capabilities of HPCs decrease as progressive
differentiation and cell lineage restrictions occur. When
measured in an in vitro cell culture assay, HPCs are referred
to as colony-forming units (CFUs). HPCs that rapidly proliferate,
retain their ability to migrate, and form multiple subcolonies
around a larger central colony in culture are called
burst-forming units (BFUs). Colony-forming unit-granulocyte,
RBC, macrophage, megakaryocyte (CFU-GEMM) is a
tetrapotential HPC that has been studied extensively in vitro .
The existence of a bipotential HPC (CFU-GM) that is the
precursor of both neutrophils (and possibly other granulocytes)
and monocytes is well established, and recent studies
indicate the likelihood of a bipotential HPC for RBCs and
megakaryocytes ( Kaushansky, 2006a ).
B . Hematopoietic Microenvironment
Blood cell production occurs throughout life in the bone
marrow of adult animals because of the unique microenvironment
present there. The hematopoietic microenvironment
is a complex meshwork composed of stromal (fibroblastlike)
cells, endothelial cells, adipocytes, macrophages, subsets
of lymphocytes, natural killer cells, and osteoblasts;
extracellular matrix components; and glycoprotein growth
factors that profoundly affect HSC and HPC engraftment,
survival, proliferation, and differentiation ( Abboud and
Lichtman, 2006 ).
Stromal cells and endothelial cells produce components
of the extracellular matrix (ECM), including collagen fibers,
basement membranes of vessels and vascular sinuses, proteoglycans,
and glycoproteins. In addition to providing
structural support, the ECM is important in the binding of
hematopoietic cells and soluble growth factors to stromal
cells and other cells in the microenvironment so that optimal
proliferation and differentiation can occur by virtue of these
cell-cell interactions.
Collagen fibers produced by stromal cells may not have
direct stimulatory effects on hematopoiesis but rather are
permissive, promoting hematopoiesis by forming an inert
scaffolding around which the other elements of the microenvironment
are organized. Hematopoietic cells can adhere
to collagen types I and VI.
Adhesion molecules (most importantly β 1 -integrins) on
the surface of hematopoietic cells bind to ECM glycoproteins
such as vascular cell adhesion molecule-1 (VCAM-1),
hemonectin, fibronectin, laminin, tenascin, vitronectin,
and thrombospondin. The spectrum of expression of adhesion
molecules on hematopoietic cells that will differentially
bind to these ECM glycoproteins varies with the type,
maturity, and activation state of the hematopoietic cells. In
addition to anchoring cells to a given microenvironmental
niche, binding of adhesion molecules on hematopoietic
cells also plays a role in cell regulation by direct activation
of signal pathways for cell growth, survival, and differentiation
or by modulating responses to growth factors.
Proteoglycans consist of a protein core with repeating
carbohydrate glycosaminoglycans (GAGs) attached.
Major proteoglycans in the marrow include heparan sulfate,
chondroitin sulfate, hyaluronic acid, and dermatan sulfate.
Proteoglycans enhance hematopoiesis by trapping soluble
growth factors in the vicinity of hematopoietic cells and
by strengthening the binding of hematopoietic cells to the
stroma.
Hematopoietic cells develop in microenvironmental
niches within the marrow. HSCs are concentrated near trabecular
bone where osteoblasts help regulate their numbers
( Yin and Li, 2006 ). Erythroid cells develop around macrophages,
megakaryocytes form adjacent to sinusoidal endothelial
cells, and granulocyte development is associated
with stromal cells located away from the vascular sinuses
(Abboud and Lichtman, 2006 ; Kaushansky, 2006a ).
C . Hematopoietic Growth Factors
Proliferation of HSCs and HPCs cannot occur spontaneously
but requires the presence of specific hematopoietic
growth factors (HGFs) that may be produced locally in
the bone marrow (paracrine or autocrine) or produced by
peripheral tissues and transported to the marrow through
the blood (endocrine). All cells in the hematopoietic microenvironment,
including the hematopoietic cells themselves,
produce HGFs or inhibitors of hematopoiesis. Some HGFs
have been called poietins (erythropoietin and thrombopoietin).
Other growth factors have been classified as colonystimulating
factors (CSFs) based on in vitro culture studies.
Finally, some HGFs have been described as interleukins
(ILs) ( Kaushansky, 2006b ).
Hematopoietic cells coexpress receptors for more than
one HGF on their surface. The number of each receptor
type present depends on the stage of cell activation and differentiation.
Binding of an HGF to its receptor results in a
series of enzymatic reactions that generate signals that promote
the synthesis of molecules that inhibit apoptosis, the
formation of cell-cycle regulators (cyclins), and the synthesis
of additional HGFs and their receptors ( Kaushansky,
2006b ).
HGFs vary in the type(s) of HSCs or HPCs that they
can stimulate to proliferate. Factors are often synergistic in
their effects on hematopoietic cells. In some instances, an
HGF may not directly stimulate the proliferation of a given
cell type but may potentiate its proliferation by inducing
the expression of membrane receptors for HGFs that do
stimulate proliferation. Some glycoproteins such as IL-1
and tumor necrosis factor- α (TNF-α ) can modulate hematopoiesis
indirectly by stimulating marrow stromal cells,