Cardiovascular System – Hematopoiesis

Chapter 20: The Cardiovascular

System: Blood
Embryology Atlas

Hematopoiesis
by John F. Neas: Stem Cells

Hematopoiesis is the process of blood cell

formation. All formed elements of the blood (blood
cells) develop from mesenchyme (mesoderm).
Blood cell formation is similar in all embryonic
sites. The parent tissue is mesenchyme that has
specializations besides hematopoiesis. At any
hematopoietic focus, some mesenchymal cells
become circulating basophilic proliferative stem
cells, or hemocytoblasts, that divide to produce all
blood cell types.
The primitive mesenchyme of the embryo
differentiates into three types of tissues: blood
islands, endothelium (both on the yolk sac), and
fixed mesenchyme cells. The primitive blood cells of
the yolk sac predominantly become early
generations of large, nucleated red blood cells that
serve the embryo for a time and then disappear. The
early endothelium soon loses its capacity to form
blood elements. Mesenchyme is the principal
hematopoietic tissue of the embryo. Its successor,
the fixed connective tissue cells of the
reticuloendothelial system, performs hematopoiesis
in the adult.

Stages of Intrauterine Hematopoiesis

Blood cells appear in the circulation during the
third week of development. Their numbers increase
as they divide repeatedly. As other organ systems

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appear, some embryonic blood cells move from the

circulation to the liver, spleen, thymus, and bone
marrow. These embryonic cells differentiate into
stem cells that produce blood cells through mitotic
divisions.
During the primordial (prehepatic) phase, human
blood stem cells develop from blood vessel
endothelium (mesoderm) of the yolk sac and
allantois. Only cells of the red cell lineage are
present.
During the hepatosplenothymic phase (beginning
in the second month), blood forms in mesenchyme
within the liver and later in the spleen and thymus.
The liver produces precursor cells of granulocytes,
megakaryocytes, and definitive erythroblasts until
its activity decreases about the fourth or fifth
month. The spleen mainly produces cells of the
erythroid lineage with fewer granulocytes and
platelets until about the seventh or eighth prenatal
month. The thymus forms only lymphocytes during
the second prenatal month.
The medullolymphatic phase begins once bone
marrow and lymph nodes develop. The clavicle is
the first bone to exhibit hematopoietic activity
(between the second and third months of
development). The marrow of other bones soon
begins to function as prenatal ossification
accelerates. By the fifth month, bone marrow
becomes the predominant hematopoietic tissue.
After birth, red bone marrow is the single source of
red blood cells and granular leukocytes. Lymph
nodes primarily produce lymphocytes.

Erythropoiesis
Erythropoiesis is the formation of erythrocytes.
Erythrocytes, or red blood cells (RBCs), develop from

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mitotic division of totipotent hemocytoblasts in the

yolk sac wall, liver, lymphoid tissue and bone
marrow of the embryo. (In adults, erythropoiesis
occurs mainly within the myeloid tissue of the bone
marrow.) Formation of RBCs increases under
stimulation by the hormone erythropoietin. Stages
in RBC development include erythroblasts and
reticulocytes.
The basic process in maturation involves (1)
decrease in cell volume; (2) diminishment in size of
nucleoli; (3) decrease in diameter, pyknosis, and
extrusion of the nucleus; (4) increase in number of
polyribosomes and hemoglobin within the
cytoplasm; and (5) decrease in quantity of
mitochondria. Ultimately, the small red corpuscle
achieves the greatest possible area for the diffusion
of oxygen. The hemocytoblasts in the yolk sac wall
produce a generation of primitive erythroblasts that
transform into primitive erythrocytes. Subsequently,
the hemocytoblasts give origin to a different,
apparently independent lineage of definitive
erythrocytes. Stages in this metamorphosis in order
of occurrence are proerythroblasts, basophilic
erythroblasts, polychromatophilic erythroblasts,
orthochromatophilic erythroblasts, reticulocytes,
and erythrocytes.
Primitive erythroblasts are capable of multiplying
by mitosis, until their nuclei become pyknotic and
extruded. These become primitive erythrocytes
once hemoglobin appears. Definitive erythroblasts,
distinctly smaller than primitive erythroblasts,
develop from hemocytoblasts in the yolk sac wall at
about the sixth week. They later develop in the liver,
and still later in the spleen and bone marrow.
Orthochromatophilic erythroblasts have nearly the
same amount of hemoglobin as mature
erythrocytes. These cells are the smallest of the

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nucleated erythrocyte precursors and have small

pyknotic nuclei. The cells will eventually extrude the
nuclei. Orthochromatophilic erythroblasts are
incapable of mitosis. Reticulocytes are the cells that
remain following loss (extrusion) of the nucleus.
These cells still contain polyribosomes to synthesize
the hemoglobin necessary to complete maturation
of the erythrocyte.

Fetal Hemoglobin
Fetal hemoglobin appears at 3 months and is the
dominant form synthesized during the
hepatosplenothymic period. Fetal hemoglobin has
two g -chains (a 2, g 2) instead of two b -chains (a 2,
b 2) as in adult hemoglobin and has greater affinity
for oxygen.
The concentration of hemoglobin, like the
erythrocyte count, increases throughout pregnancy
to improve the total oxygen capacity of fetal blood.
This high level falls rapidly to a nadir two to three
months after birth. A normal decrease in production
of red blood cells by bone marrow produces this self-
limiting physiologic anemia.
At birth, blood hemoglobin is about 70% of the
fetal type. Very little fetal hemoglobin is detectable
in most children by the end of their first postnatal
year. Adult hemoglobin appears during the second
trimester (about the sixth month).

Leukopoiesis
Leukopoiesis is the formation of white blood cells.
Granulocytes and monocytes are produced by stem
cells (hemocytoblasts) in the bone marrow. Stem
cells responsible for lymphopoiesis also originate in
the bone marrow, but many migrate to peripheral
lymphoid tissues. The bone marrow and the thymus

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are primary lymphoid organs. Secondary lymphoid

organs, such as the spleen, tonsils, or lymph nodes,
have white blood cells that divide to produce cells of
the same type.

Granulocytopoiesis
Granulocytopoiesis begins during the second
month in the mesenchyme of the liver. Later,
granulocytes develop entirely from red marrow.
The subsequent stages in development of
granulocytes include four mitotic stages (stem cell,
myeloblast, promyelocyte, myelocyte) followed by
three maturation stages (metamyelocyte, band cell,

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mature granulocyte). The myeloblast is the most

immature cell in myeloid series that is recognizable.
Band cells and mature granulocytes (basophils,
eosinophils, and neutrophils) are the only forms that
normally occur in circulation.
Promyelocytes have granules but a kind different
from the specific granules in myelocytes. When
specific cytoplasmic granules appear, the cells are
eosinophilic, basophilic, or neutrophilic myelocytes.
Myelocytes first appear in the blood at about the
twelfth week. Metamyelocytes have deeply indented
nuclei that indicate the beginning of lobe formation.
Nuclear activity, protein synthesis, and related
organelles decrease during this stage of
development as the chromatin condenses into
heterochromatin. Before becoming mature cells with
lobate nuclei, granulocytes have nuclei that appear
as curved rods (band cells).
Mature granulocytes first appear in the peripheral
blood at three months. All types can ingest foreign
material. Neutrophils have finely granular, neutrally
staining (purple) cytoplasm and complexly lobate
nuclei. Neutrophils provide an important defense
against infection. Eosinophils have a bilobed nucleus
and coarse granulations that stain intensely orange-
red with acid dyes. Eosinophils participate in allergic
responses. Basophils acquire an irregularly shaped
nucleus and differentiate coarse cytoplasmic
granules that stain heavily purple-black with basic
dyes. Basophils contain histamine and heparin.

Lymphocytopoiesis
Lymphopoiesis is the production of lymphocytes.
Lymphoblasts, the first identifiable progenitors of
lymphoid cells, arise at about the eighth week from
hemocytoblasts or directly from mesenchyme

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around lymph vessels. They develop from stem cells

originating in bone marrow that transport through
the blood and take residence in lymphoid organs
(thymus, spleen, lymph nodes, tonsils) where they
appear at about the twelfth week. In addition, they
briefly form during embryonic life in the liver, but
not in the wall of the yolk sac.
Lymphoblasts divide two to three times to form
smaller prolymphocytes that have relatively more
condensed chromatin but none of the cell-surface
antigens of T- or B-lymphocytes. Some relatively
undifferentiated lymphocytes migrate to the thymus
where they acquire attributes of T lymphocytes and
subsequently populate specific regions of peripheral
lymphoid organs. Other bone marrow lymphocytes
remain in the marrow and differentiate into B-
lymphocytes. These migrate to peripheral lymphoid
organs where they populate special compartments.
Lymphocytes appear in the fetal blood at about the
end of the second month.
Factors that regulate lymphocyte maturation are
incompletely known. Several colony-stimulating
factors (CSF’s) are involved in regulating WBC
populations and coordinating RBC and WBC
production.

Monocytopoiesis
The committed progenitor cell of the monocyte
series, the monoblast, arises from the
hemocytoblast during the fifth month. Monoblasts
are virtually identical in morphology to myeloblasts.
Further differentiation produces promonocytes, large
cells with basophilic cytoplasm and large slightly
indented nuclei and obvious nucleoli. Promonocytes
divide twice to become monocytes. Monocytes have
a characteristic kidney-shaped nucleus, a large

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amount of rough endoplasmic reticulum, and an

extensive Golgi complex for production of
lysosomes. Mature monocytes enter the blood,
circulate for about 8 hours, and then enter
connective tissue where they mature into
macrophages that function for several months.

Megakaryocytopoiesis
Some hemocytoblasts differentiate very early into
megakaryoblasts with large polyploid nuclei and
numerous nucleoli. These, in turn, differentiate into
even larger megakaryocytes with irregularly
lobulated nuclei and no visible nucleoli. Red bone
marrow becomes the source and site of these cells
by the fourth month. Megakaryocytes are the giant
cells typically found in bone marrow, and they
distribute through the blood to the liver and spleen.
Platelets (thrombocytes) arise by membrane fusion
and fragmentation from the megakaryocytic
cytoplasm. Platelets are difficult to find until the
second half of pregnancy. They reach adult numbers
by birth.

©2003 Pearson Education, Inc., publishing as Benjamin Cummings