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

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Chapter | 7 The Erythrocyte: Physiology, Metabolism, and Biochemical Disorders
endothelial cells, and T cells to produce HGFs. Different
combinations of HGFs regulate the growth of different
types of HSCs or HPCs ( Kaushansky, 2006a ).
Early-acting HGFs are involved with triggering dormant
(G O ) primitive HSCs to begin cycling. Stem cell factor
(SCF), flt3 ligand (FL), and thrombopoietin are important
early factors that act in combination with one or more other
cytokines such as IL-3, IL-6, IL-11, and granulocyte-CSF
(G-CSF).
Intermediate-acting HGFs have broad specificity. IL-3
(multi-CSF), granulocyte-macrophage-CSF (GM-CSF), and
IL-4 support proliferation of multipotent HPCs. These factors
also interact with late-acting factors to stimulate proliferation
of a wide variety of committed progenitor cells.
Late-acting HGFs have restricted specificity. Macrophage-
CSF (M-CSF), G-CSF, erythropoietin, thrombopoietin, and
IL-5 are more restrictive in their actions. They have their
most potent effects on committed progenitor cells and later
stages of development when cell lines can be recognized
morphologically ( Kaushansky, 2006b ).
D . Erythropoiesis
1 . Primitive Erythropoiesis
Primitive RBC production begins and predominates in the
yolk-sac but also occurs later in the liver and bone marrow.
Primitive RBCs are large ( 400 fl in humans) generally
nucleated cells with high nuclear-to-cytoplasmic ratios.
Their nuclei have open (noncondensed) chromatin, and their
cytoplasm contains predominantly embryonal Hb with high
oxygen affinity ( Segel and Palis, 2006 ; Tiedemann, 1977 ;
Tsuji-Takayama et al. , 2006 ). Like nonmammalian species,
primitive RBCs enter blood as nucleated cells, but in contrast
to nonmammalian species, enucleation can eventually
occur in the circulation ( Kingsley et al. , 2004 ). Primitive
RBCs appear to be generated in an erythropoietin (Epo)-
independent manner, but their expansion and survival require
Epo ( Tsuji-Takayama et al. , 2006 ). A switch to definitive
erythropoiesis occurs during fetal development. Definitive
erythropoiesis results in the production of smaller cells that
generally extrude their nuclei before entering blood, produce
fetal Hb (in some species) and adult Hb, and are highly
dependent on Epo ( Tsuji-Takayama et al. , 2006 ).
2 . Defi nitive Erythropoiesis
Oligopotent progenitor cells (including CFU-GEMM cells)
are stimulated to proliferate and differentiate into BFU-E
by SCF, IL-3, and GM-CSF in the presence of Epo. BFU-E
proliferation and differentiation into CFU-E results from the
presence of these same factors and may be further potentiated
by additional growth factors. Epo is the primary growth factor
involved in the proliferation and differentiation of CFU-E
into rubriblasts, the first morphologically recognizable
erythroid cells. CFU-E cells are more responsive to Epo than
are BFU-E cells because CFU-E cells exhibit greater numbers
of surface receptors for Epo ( Sawada et al. , 1990 ).
Marrow macrophages are important components of the
hematopoietic microenvironment involved with erythropoiesis.
Both early and late stages of erythroid development
occur with intimate membrane apposition to central macrophages
in so-called blood islands. Several adhesion molecules
are important in forming these blood islands ( Chasis,
2006 ). These central macrophages may regulate basal RBC
production by producing both positive growth factors,
including Epo, and negative factors such as IL-1, TNF- α ,
transforming growth factor- β , and interferon- α , -β , and - γ
(Chasis, 2006 ; Weiss and Goodnough, 2005 ; Zermati et al. ,
2000 ). The finding that Epo can also be produced by erythroid
progenitors suggests that these cells may support
erythropoiesis by autocrine stimulation ( Stopka et al. ,
1998 ). Although some degree of basal regulation of erythropoiesis
occurs within the marrow microenvironment,
humoral regulation is important, with Epo production
occurring primarily within peritubular interstitial cells of
the kidney and various inhibitory cytokines being produced
at sites of inflammation throughout the body.
3 . Erythropoietin
Epo is a 34 kDa glycoprotein hormone that exhibits a
high degree of sequence homology among mammals
( Wen et al. , 1993 ). It is the principal HGF that promotes
the viability, proliferation, and differentiation of erythroid
progenitor cells expressing specific cell surface Epo receptors.
The main mechanism used to achieve these effects is
inhibition of apoptosis. The binding of Epo to its receptor
results in autophosphorylation of the receptor and the
activation of several kinases that initiate multiple signaling
pathways ( Eckardt and Kurtz, 2005 ). Early BFU-E cells
do not express Epo receptors, but more mature BFU-E
cells express Epo receptors and are responsive to Epo.
Epo receptor copies on cell surfaces increase to maximum
values in CFU-E cells and then decline in rubriblasts and
continue to decrease in later stages of erythroid development
( Porter and Goldberg, 1993 ; Prchal, 2006 ). Because
of their Epo receptor density, CFU-E cells readily respond
to Epo, promoting their proliferation, differentiation, and
transformation into rubriblasts, the first morphologically
recognizable erythroid cell type. High concentrations of
Epo may accelerate rubriblast entry into the first mitotic
division, shortening the marrow transit time and resulting
in the early release of stress reticulocytes ( Prchal, 2006 ).
In the presence of Epo, other hormones including androgens,
glucocorticoid hormones, growth hormone, insulin,
and insulin-like growth factors (IGFs) can enhance the
growth of erythroid progenitor cells in vitro (Leberbauer
et al. , 2005 ; Miyagawa et al. , 2000 ). However, growth
factors may have additional effects in vivo . For example,