CHAPTER 8
Blood and Hemopoiesis
145
Hemopoiesis
Introduction and Key Concepts
for Hemopoiesis
All formed elements, with the exception of some lymphocytes,
have a F nite life span in circulation, so there must be an ongoing
replacement throughout the life of an individual. The magnitude
of the task for a given cell type can be appreciated if the approxi-
mate required daily production rate is calculated from estimates
of the total number in circulation and the rate of turnover for the
cell type. ±or
erythrocytes
, with a life span of about 120 days,
the daily production rate is roughly 250 billion, for
neutrophils
,
with a time in circulation of less than a day, the daily production
rate is normally roughly 60 billion, and for
platelets
, with a life
span of about 10 days, the daily production rate is approximately
150 billion. The development of each type of blood cell involves
numerous cell divisions and a series of differentiation steps so that
a small number of completely undifferentiated stem cells pro-
duce enormous numbers of cells that have the speciF c equipment
necessary for the particular mature cell to perform its functions.
Although all blood cells originate from a common
pluripotential
hemopoietic stem cell
, each blood cell type has its own lineage of
cell generations committed to proliferate and, at the same time,
differentiate only into that cell type. Cells that can be recognized
morphologically as undertaking differentiation into a particular
blood cell are called
precursor cells
. Precursor cells are produced
by cells that are committed to a speciF c lineage (i.e., they are
determined to give rise to, e.g., only erythrocytes) but show no
morphological signs of differentiation. These are called
progenitor
cells
. Some progenitor cells are not restricted in potential to just
one blood cell lineage but rather to two lineages. Progenitor cells
are also termed
colony-forming cells
(
CFCs
). A commonly used
abbreviation system for designating speciF c progenitor cells uses
the F rst letter of the blood cell name after the letters C±C, for
example,
CFC-E
for
erythrocyte colony–forming cell
and
CFC-B
for
basophil colony–forming cell
. Development of blood cells
occurs mostly in the specialized environment of the bone marrow.
Because extensive cell proliferation is required, the process is very
vulnerable to irradiation, so protection within the cores of bones
is clearly advantageous. The development of each type of blood
cell involves a series of precursor cells that can be recognized in
smears of the red bone marrow that have been stained with the
same procedures used for peripheral blood smears.
Lymphocytes
and
monocytes
are little differentiated, so the morphological
appearance of their precursors (
lymphoblasts
and
promonocytes
,
respectively) is not easily distinguished. By contrast, the precursors
of
erythrocytes
,
granulocytes
, and
platelets
exhibit relatively dis-
tinct features as they differentiate in a series of steps that involve
predictable changes and identiF able stages. The red bone marrow
is a hemopoietic compartment where blood cells (except lympho-
cytes) develop and mature (±ig. 8-15C).
ERYTHROCYTE DEVELOPMENT
is called
erythropoiesis
.
The appearances of the
precursors
of
erythrocytes
refl ect the pro-
cesses that must take place to generate, from an undifferentiated
cell, a cell that is essentially a plasmalemma bag of hemoglobin. In
the initial stage, the
proerythroblast
, the main event is generation of
free ribosomes that will be needed to synthesize the globin that will
combine with heme to form hemoglobin. Therefore, the intense
basophilic staining of the cytoplasm in the next stage, the
basophilic
erythroblast
, results from a peak concentration of free ribosomes
that begin translation of globin mRNAs. In the
polychromatophilic
erythroblast
, enough
hemoglobin has accumulated to confer some
eosinophilia
to the cytoplasm, whereas the concentration of
ribo-
somes
has decreased from dilution that accompanies cell division.
Continuation of cell division, dilution of ribosomes, and accumu-
lation of more hemoglobin account for the strong eosinophilic
staining of the cytoplasm in the
orthochromatophilic erythroblast
(
normoblast
). Concurrent with the successive changes in staining of
the cytoplasm during erythrocyte development in the cytoplasm are
changes in the appearance of the nucleus. Production of ribosomes
and transcription of mRNA for globin and other proteins are man-
ifested by a large
euchromatic nucleus
with prominent nucleoli in
the
proerythroblast
; subsequent stages have progressively smaller,
less active nuclei, and the nucleus is ultimately extruded at the end
of the
orthochromatophilic erythroblast
stage. The mitochondrion,
another key organelle, is required to synthesize
protoporphyrin
and
combine it with iron to form the heme of
hemoglobin
(±igs. 8-9A
and 8-10A to 8-11C).
PLATELET DEVELOPMENT
is called
thrombopoiesis
.
Although
platelets
are small (2–4
μ
m in greatest diameter) frag-
ments of highly organized cytoplasm, they are produced by
very large cells called
megakaryocytes
. These cells measure up
to 100
μ
m or more in diameter. Megakaryocytes develop from
precursor cells (called
megakaryoblasts
) through a series of
incomplete cell cycles (
endomitosis
) that do not include division
of the nucleus or cytoplasm. The result is that the nucleus of a
mature megakaryocyte has up to 64N chromosomes, instead
of the usual 2N chromosomes. The nucleus is large and lobu-
lar, but it remains one nucleus. The cytoplasm develops numer-
ous mitochondria, a variety of granules, and microF
laments
and microtubules. As the megakaryocyte reaches maturity, its
cytoplasm becomes cordoned off by an elaborate system of
membranes, called
demarcation membranes
or
channels
, which
subdivide the
cytoplasm into platelet zones—like perforations
in a sheet of stamps (±igs. 8-9B and 8-12A–C).
GRANULOCYTE DEVELOPMENT (GRANULOCYTOPOI-
ESIS)
proceeds through an orderly sequence of events that
result in cytoplasm that is packed with granules containing a
wide variety of substances related to infl ammation and destruc-
tion of pathogenic organisms. As is the case with erythrocyte
development, the initial discernible event is generation of com-
ponents (
ribosomes
and
RNA
) needed for protein synthesis,
but in granulocyte development, the proteins will be packaged
in
vesicles
(
granules
). Accordingly, packaging of the proteins
requires development of an extensive
endoplasmic
reticulum
and
Golgi complex
. These events are prominent in the
myelo-
blast
and
promyelocyte
stages, both of which have relatively
large, active nuclei with nucleoli and cytoplasm that is baso-
philic owing to its content of ribosomes. Granule generation
occurs sequentially, the
nonspeci± c (lysosomal) granules
F rst,
in the promyelocyte stage, and the
speci± c granules
second, in
the myelocyte stage. Because speciF c granules F
rst appear in the
myelocyte stage, this is the earliest stage at which the precur-
sors of the three granulocytes can be distinguished from each
other. Other notable changes during granulocyte maturation are
progressive condensation, elongation, and segmentation of the
nucleus (±igs. 8-13A to 8-15B).
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