HEMA 1A Lec 1st Shift Reviewer
Hematopoiesis
Prepared by: C3
HEMATOPOIESIS DEFINED
• Hematopoiesis is the process of blood
cell production, differentiation, and
development
• The hematopoietic system includes:
o Bone marrow
o Liver
o Spleen
o Lymph nodes
o Thymus
ORIGIN OF BLOOD CELLS
Types of Human Stem Cells
1. Totipotential Stem Cells
• Present in the first few hours
after an ovum is fertilized
• The most versatile type of stem
cell
• Can develop into any human
cell type (e.g. embryo to fetus)
2. Pluripotential Stem Cells
• Present several days after
fertilization
• Develop into any cell type,
except they cannot develop into
a fetus
3. Multipotential Stem Cells
• Derived from pluripotent stem
cells
• Found in adults but are limited
to specific types of cells to form
tissues
Early Development of Blood Cells
• Embryonic blood cells, excluding the
lymphocyte type of WBC, originate from
the mesenchymal tissue that arises from
the embryonic germ layer, the
mesoderm
• The Aorta-Gonad-Mesonephros
Region (or paraaortic splanchnopleure),
produces potent HSCs and multipotent
progenitor cells before appearing in the
yolk sac, respectively
• The anatomical sites of blood cell
development are as follows:
o Following gastrulation and
mesoderm formation, the first
hematopoietic cells are
generated in the yolk sac. The
first blood cells are primitive red
blood cells (erythroblasts)
formed during the first 2 to 8
weeks of life
o The onset of circulation between
the yolk sac and embryo proper
confounds the precise
determination of hematopoietic
sources. Mesenchymal
stem/progenitor cells and HSCs
circulate together in the
peripheral blood during the first
trimester to the secondary
ontogenic sites of
hematopoiesis, the liver and the
bone marrow. Gradually, the
liver becomes the site of blood
cell development. By the second
month of gestation, the liver
becomes the major site of
hematopoiesis, and granular
types of leukocytes have made
their initial appearance. The
liver predominates from about
the second to fifth months of
fetal life.
o In the fourth month of gestation,
the bone marrow begins to
function in the production of
blood cells. After the fifth fetal
month, the bone marrow begins
to assume its ultimate role as
the primary site of
hematopoiesis (medullary
hematopoiesis).
TRIPLE C NOTES 1
 sternum, skull bones, pelvis,
and to some extent the proximal
epiphyses of the femur and
humerus
• Extramedullary Hematopoiesis
o Spleen, liver, and lymph nodes
revert back to producing
immature blood cells
o Enlargement of spleen and liver
occurs
o Undifferentiated primitive blood
cells are present in these areas
Figure 1. Hematopoiesis in various organs before and and are able to proliferate if an
after birth. appropriate stimulus is present
o Occurs when the bone marrow:
BONE MARROW SITES AND  Becomes dysfunctional
FUNCTION in cases such as
• Found within the cavities of all bones aplastic anemia,
• May be present in 2 forms: infiltration by malignant
o Yellow Marrow cells, or
 Normally inactive overproliferation of a
 Composed mostly of cell line (e.g. leukemia)
adipose tissue  Is unable to meet the
o Red Marrow demands placed on it,
 Normally active in the as in the hemolytic
production of most anemias
types of RBCs, WBCs,
and Platelets (see
Figure 2)
• One of the body’s largest organs
o Represents 3.5-6% of total body
weight and averages around
1,500 g in adults
o Hematopoietic marrow is
organized in the bone
vasculature (see Figure 3)
• Consists of the hematopoietic cells
(erythroid, myeloid, lymphoid, and Figure 2. Normal Bone Marrow Biopsy.
megakaryocyte), adipose tissue,
osteoblasts and osteoclasts, and stroma
• During the first few years of life, the
marrow of all bones is red and cellular
o Initially found in both
appendicular and axial
skeletons in young persons but
progressively becomes confined
to the axial skeleton and
proximal ends of long bones in
adults
o By age 18, red marrow is found
only in the vertebrae, ribs, Figure 3. The development of blood cells: humerus
bone, cortical bone, red, and yellow bone marrow.

TRIPLE C NOTES 2
CELLULAR ELEMENTS OF BONE
MARROW
Progenitor Blood Cells
• The pluripotent stem cell is the first in a
sequence of steps of hematopoietic cell
generation and maturation
• The progenitor of all blood cells is called
the multipotential hematopoietic stem
cell
• Stem cells have the capacity for self-
renewal as well as proliferation and
differentiation into progenitor cells
• “Stem Cell Plasticity” is a concept where
stem cells are amazingly adaptable and
are able to generate an assortment of
seemingly unrelated types of cells
• “Multipotent Adult Progenitor Cells”
(MAPCs) are master cells which express Figure 4. General Model of Hematopoiesis where
an enzyme called telomerase that keeps blood cell development progresses from an HSC.
cells from aging
• Hematopoietic cells can be divided into Erythropoiesis
3 phases according to cell maturity • Occurs in distinct anatomical sites called
o Primitive, Multipotential Cells Erythropoietic Islands, specialized
 The most immature niches in which erythroid precursors
group capable of self- proliferate, differentiate, and enucleate
renewal and o Each island consists of a
differentiation into all macrophage surrounded by a
blood cell lines cluster of erythroblasts
o Intermediate Cells • Erythroid cells account for 5-38% of
 This group consists of nucleated cells in the normal bone
committed progenitor
cells destined to
Granulopoiesis
develop into distinct cell
• Myeloid cells account for 23-85% of the
lines
nucleated cells in normal bone marrow
o Mature Cells
• Recognized as a maturational unit
 The most developed
group with specific • Maturing cells spend 3-6 days in the
functions proliferating pool and can exit into the
circulation rapidly with a 6-10 hour
• Hematopoietic Progenitor Cells
lifespan
(HPCs) can be mobilized from the bone
marrow to the blood by a wide variety of
stimuli, including hematopoietic growth Lymphopoiesis
factors and chemokines • Unlike other cell lines, lymphocytes and
plasma cells are produced in lymphoid
follicles
• Lymphoid cells account for 1-5% of the
nucleated cells in the normal bone
marrow

TRIPLE C NOTES 3
Megakaryopoiesis
• Takes place adjacent to the sinus
endothelium
• Megakaryocytes protrude through the
vascular wall as small cytoplasmic
processes to deliver platelets into the
sinusoidal blood
o Develop into platelets in
approximately 5 days
Other Cells Found in Bone Marrow
Marrow Stromal Cells
• Composed of reticulum cells,
histiocytes, adipose cells, and
endothelial cells
• Structure where hematopoietic
cells are suspended in a
delicate semifluid state
Mast Cells
• Connective tissue cells of
mesenchymal origin
• Normally observed in the bone
marrow
• Increased numbers can be seen
in a variety of abnormal
conditions (e.g. chronic
infections)
Macrophages
• Also called reticulum cells or
histiocytes
• Appear as large cells in the
bone marrow
• The appearance of the
cytoplasms will vary, depending
on what the cell has ingested
Bone Cells
• Also called osteoblasts
• Bone matrix-synthesizing cells
that resemble plasma cells and
are usually observed in groups
• Osteoclasts resemble
megakaryocytes
o Bone-remodeling cells
INTERLEUKINS
• Protein molecules that work in
conjunction with hematopoietic growth
factors to stimulate proliferation and
differentiation of specific cell lines
• Cytokines that act independently or in
conjunction with other interleukins to
encourage hematopoietic growth
• Cell signaling molecules and a part of
the cytokine super family of signaling
molecules
• First described as signals for
communication between (inter-between)
white blood cells (leuk-from leukocytes)
• Method of immune cross-talk and
communication
• Primary messengers and directors of the
immune system
• There are 35 known interleukins
however there are many more to be
found and characterized
• They can cause:
o Cellular proliferation
o Cell activation
o Inflammation
o Physiological changes (e.g.
fever, pain)
o Allergies as with histamine
release and growth
HEMATOPOIETIC GROWTH
FACTORS
• Each hematopoietic growth factor is
encoded by a single gene
• The gene for erythropoietin is located on
chromosome 7
• The major role of hematopoietic growth
factors appear to be regulating the
proliferation and differentiation of HPCs
as well as regulating the survival and
function of mature blood cells
o Biological effects are mediated
through specific binding
receptors on the surface of
target cells
• Used and tested in clinical trials for the
treatment of a variety of hematological
disorders
• Capable of mobilizing HPCs
• A striking feature of growth factors is the
diversity of the target population.
Examples of various factors and the
target cells are:
TRIPLE C NOTES 4
 o G-CSF and GM-CSF
predominantly affect myeloid Nuclear Characteristics
cells Chromatin Patterns
o IL-7 stimulates T and B • Demonstrates characteristic
lymphocytes patterns in terms of maturity and
o IL-12 targets natural killer cells cell type recognition
• The mobilization of HPCs from the bone • In general, the overall pattern
marrow to the peripheral blood progresses from a loose-looking
circulation is a complicated process arrangement to a more clumped
regulated by multiple adhesive pattern as a cell matures
interactions between the HPCs and the • Terms used:
bone marrow extracellular matrix o Smooth or
homogeneous
o Fine
o Delicate
o Lacy or thready
o Smudged
o Clumped
Figure 5. Characteristics of Human Hematopoietic o Pyknotic (dense or
Growth Factors compact)
• Examples:
EXAMINATION OF MATURING o Lymphocytes exhibit a
smooth or
BLOOD CELLS
homogeneous pattern
• A comprehensive examination of bone
of chromatin throughout
marrow involves examination of both
development until the
bone marrow smears and histological mature stage, when
tissue sections clumped
• The examination of a stained peripheral heterochromatin is more
blood smear is an important component obvious
of the complete blood count (CBC) o Granulocytes progress
from having a fine to a
General Cellular Characteristics highly clumped pattern
Overall Cell Size o Monocytes have a lacy
• Except for the megakaryocytic pattern, which becomes
maturational series, finer as the cell matures
erythrocytes and leukocytes o Erythrocytes continue to
decrease in overall size as develop a more
maturation progresses clumped pattern as
Nuclear-Cytoplasmic Ratio (N:C) maturation progresses,
• The amount of space occupied until the extremely
by the nucleus in relationship to dense (pyknotic)
space occupied by the nucleus is lost
cytoplasm (extruded) from the
• The size of the nucleus mature cell
generally decreases as a cell Nuclear Shape
matures • Usually in young cells, it is
o Consequently, the N:C round or oval
Ratio decreases in o Monocytes have a
many cell types with slightly folded nuclear
maturation shape

TRIPLE C NOTES 5
 • Nuclear shape becomes
distinctive for those that retain
their nucleus
o Lymphocytes usually
continue to have a
round or oval nucleus.
Some cells may have a
small cleft in the
nucleus
o Monocytes have a
kidney bean-shaped
nucleus, but folded or
horseshoe shapes are
common
o Mature neutrophils,
eosinophils, and
basophils have
segmented nuclei
attaches to one another
by fine filaments
Presence of Nucleoli
• Generally not visible in mature
cells
• Present in earliest cell stages of
erythrocytes, leukocytes, and
megakaryocytes
• Related to the rate of synthesis
of ribosomal RNA
• Examples:
o Lymphoblasts have 1-2
nucleoli
o Myeloblasts have 1-5
nucleoli
o Monoblasts usually
have 1-2 but
occasionally may have
3-4 nucleoli
o Erythroblasts may have
0-2 nucleoli that may
stain darker than in
other types of blast cells
o Megakaryoblasts
typically have 1-5
nucleoli
Cytoplasmic Characteristics
Staining Color and Intensity
• Varies with cell maturity and
type
• In general, cytoplasmic color
progresses from darker blue
(indicating active protein
synthesis) in younger cells to
lighter blue or pink in mature
cells
• Immature erythrocytes have a
very distinctive dark-blue
cytoplasm that becomes paler
and gray looking as the cell
synthesizes hemoglobin
• As mature cells, lymphocytes
are usually noted for their pale
sky-blue cytoplasmic color
Granulation
• Granulation progresses from no
granules to non-specific
granulation to specific
granulation
• Erythrocytes never exhibit
granulation throughout their life
cycle
• Granules vary in several ways:
o In size, ranging from
very fine to coarse
o In color, including red
(azurophilic), blue
(basophilic), and orange
(eosinophilic)
o In the amount of
granulation per cell
Cytoplasmic Shape
• The most distinctive variation in
cytoplasmic shape occurs in
some blast forms, monocytes,
and megakaryocytes
• Pseudopods may be observed
in mature monocytes and in
some leukocyte blast forms
Quantity of Cytoplasm
• Actual quantity of cytoplasm
increases with age
• Abnormalities of lymphocytes
frequently demonstrate
increased amounts of cytoplasm
Vacuolization
• Increases with age
• Except for monocytes,
vacuolization of the cytoplasm is
commonly seen in older cells
and in abnormal conditions
TRIPLE C NOTES 6
 • Anticoagulants can also
produce vacuoles as artifacts if
the blood is stored for a longer-
than-acceptable period
Inclusion Bodies
• Important to know because they
aid in the identification of cell
types
• Various erythrocytic and
leukocytic inclusions are
indicative of specific diseases
• Some may be seen on a Wright-
stained blood smear but others
require special staining
techniques

MATURE BLOOD CELLS IN

PERIPHERAL BLOOD
• Identification of blood cells by
microscopic examination of a peripheral
smear can be performed more
systematically if the morphologist
assesses the various maturational
features as outlined in the preceding
section

Figure 6. Normal adult values and selected

characteristics of mature leukocytes in peripheral
blood

TRIPLE C NOTES 7