HEALTH SCIENCE (HSCI) 1ST SEMESTER

LECTURE LESSON 7

HEMATOPOIESIS ➢ myeloid-to-erythroid ratio gradually approaches 3:1 to

➢ The continuous, regulated process of renewal,
proliferation, differentiation, and maturation of all
blood cell lines.
HEMATOPOIESIS
SITES OF HEMATOPOIESIS BY AGE
4:1 (normal adult levels)
➢ By the end of 24 weeks gestation, the bone marrow
becomes the primary site of hematopoiesis
➢ In adults, hematopoietic tissue is located in the bone
marrow, lymph nodes, spleen, liver and thymus
➢ The bone marrow contains developing erythroid,
myeloid, megakaryocytic, and lymphoid cells.
➢ Lymphoid development occurs in both primary and
secondary lymphoid tissue

STEM CELL THEORY

➢ Originally there were two theories describing the

origin of the hematopoietic progenitor cells
▪ Monophyletic Theory – suggests that all blood
cells are derived from a single progenitor stem
cell called pluripotent hematopoietic stem cell
▪ Polyphyletic Theory – suggests that each of the
blood cell lineages is derived from its own unique
stem cell.
➢ The monophyletic theory is the most widely accepted
3 PHASES OF HEMATOPOIESIS theory among experimental hematologists
1) Mesoblastic Phase DIAGRAM OF HEMOTOPOIESIS
➢ Hematopoiesis is considered to begin around the
nineteenth day of embryonic development after
fertilization
➢ Early in embryonic development, cells from the
mesoderm migrate to the yolk sac
➢ These primitive but transient yolk sac erythroblasts
are important in early embryogenesis to produce
hemoglobin (Gower-1, Gower-2, and Portland)
needed for delivery of oxygen to rapidly developing
embryonic tissues
➢ Yolk sac hematopoiesis differs from hematopoiesis
that occurs later in the fetus and adult in that it occurs
intravascularly (within developing blood vessels)

2) Hepatic Phase

➢ Begin at 5 to 7 gestational weeks and is characterized

by recognizable clusters of developing erythroblasts,
granulocytes, and monocytes colonizing the fetal liver,
thymus, spleen, placenta, and ultimately the bone
marrow space in the final medullary phase
➢ Hematopoiesis during this phase occurs extra
vascularly, with the liver remaining the major site of
hematopoiesis during the second trimester of fetal life
➢ The thymus, the first fully developed organ in the
fetus, becomes the major site of T cell production, ERYTHROPOIESIS
whereas the kidney and spleen produce B cells
➢ Occurs in the bone marrow and is complex, regulated
3) Medullary (Myeloid) Phase process for maintaining adequate numbers of
erythrocytes in the peripheral blood
➢ Begin between the fourth and fifth month of fetal ➢ Erythroid Progenitors
development ▪ Burst forming unit – Erythroid (BFU-E)
➢ Hematopoietic activity, especially myeloid activity, is ▪ Colony forming unit – Erythroid (CFU-E)
apparent during this stage of development, and the
 ➢ Erythroid Precursors
▪ The earliest morphologically recognizable
erythrocyte precursor, the pronormoblast
➢ Criteria used in identification of Erythroid Precursors
▪ Overall diameter of the cell decreases
▪ Diameter of the nucleus decreases more rapidly
than does the diameter of the cell
▪ Nuclear chromatin pattern becomes coarser,
clumped, and condensed
▪ Nucleoli disappear
▪ Cytoplasm changes from the gray-blue to salmon
pink

PRONORMOBLAST (Proerythroblast)

➢ First microscopically recognizable precursor cell in

erythropoiesis
➢ NUCLEUS: is round and oval, containing one or 2
nucleoli. The purples red chromatin is open and
contains few, if any fine clumps
➢ CYTOPLASM: Basophilic
➢ NC Ratio: High (8:1)
➢ Forms two basophilic normoblast after mitosis
➢ The pronormoblast is present only in the bone marrow
in healthy states

BASOPHILIC NORMOBLAST (Basophilic Erythroblast)

A. Diameter decreases and cytoplasm changes from ➢ NUCLEUS: the chromatin begins to condense,
blue to salmon pink revealing clumps along the periphery of the nuclear
B. Nuclear diameter decreases and color changes from membrane and a few in the interior
purplish-red to a very dark purple-blue ➢ CYTOPLASM: deeply basophilic. The cytoplasm is
C. Nuclear chromatin becomes coarser, clumped, and dark blue because of the concentration of ribosomes
condensed and RNA
D. Composite of changes during the developmental ➢ NC Ratio: Moderate (6:1)
process ➢ Undergoes mitosis, giving rise to two daughter cells
➢ Is present only in the bone marrow in healthy states
RED BLOOD CELL ➢ Detectable hemoglobin synthesis occurs
➢ Major Function: Carry Oxygen from the lung to the POLYCHROMATIC (Polychromatophilic) NORMOBLAST
tissues (Polychromatic Erythroblast)
▪ Attachment of oxygen to hemoglobin, the major
cytoplasmic component of mature RBCs ➢ NUCLEUS: The condensation of chromatin reduces
➢ Acid base buffer the diameter of the nucleus considerably
➢ Biconcave in shape ➢ CYTOPLASM: This is the first stage in which the pink
➢ Distensible color associated with stained hemoglobin can be seen
➢ NC RATIO: Moderate
Three Erythroid Precursor Nomenclature Systems ➢ Last stage which contains a nucleus
➢ Last stage capable of mitosis
Normoblastic Rubriblastic Erythroblastic
Pronormoblast Rubriblast Proerythroblast ORTHOCHROMATIC NORMOBLAST (Metarubricyte)
Basophilic Prorubricyte Basophilic
Normoblast erythroblast ➢ NUCLEUS: is completely condensed (i.e., pyknotic) or
Polychromatic Rubricyte Polychromatic nearly so
(polychromatophili (polychromatophili ➢ CYTOPLASM: pink gray (more pinkish)
c) Normoblast c) Erythroblast ▪ The increase in the salmon pink color of the
Orthochromic Metarubricyte Orthochromic cytoplasm reflects nearly complete hemoglobin
Normoblast Erythroblast production
Polychromatic Polychromatic Polychromatic ➢ NC Ratio: Low
(polychromatophili (polychromatophili (polychromatophili ➢ No longer capable of division
c) Erythrocyte c) Erythrocyte c) Erythrocyte
Erythrocyte Erythrocyte Erythrocyte POLYCHROMATIC ERYTHROCYTE (Reticulocyte)

➢ First anucleated precursor

➢ RNA synthesis stops while heme synthesis continues
➢ Loses its RNA and mitochondria
 ➢ NUCLEUS: none
➢ CYTOPLASM: Pink gray
▪ By the end of the polychromatic erythrocyte
stage, the cell is the same color as a mature
RBC, salmon pink. It remains larger than a
mature cell, however.
➢ Resides in the bone marrow for about 1 to 2 days and
then moves into the peripheral blood for about 1 day
before reaching maturity.
ERYTHROCYTES
➢ Life span: 120 days
➢ No nucleus, mitochondria, or endoplasmic reticulum
➢ The mature circulating erythrocyte is a biconcave disc
measuring 7 to 8 "m in diameter, with thickness of
about 1.5 to 2.5 "m.
➢ On a Wright-stained blood film, it appears as a
salmon-pink stained cell with a central pale area that
corresponds to the concavity. The central pallor is
about one-third the diameter of the cell.
➢ Contains Cytoplasmic enzymes capable of
metabolizing glucose
ERYTHROKINETICS
➢ Is the term describing the dynamics of RBC
production and destruction
➢ If tissue oxygen is inadequate, RBC production and
the functional efficiency of existing cells must be
enhanced
➢ The primary oxygen-sensing system of the body is
located in peritubular and fibroblasts of the kidney
➢ Hypoxia, too little tissue oxygen is detected by the
peritubular fibroblasts, which then produce
erythropoietin (EPO), the major stimulatory cytokine
for RBC
➢ It is well documented that testosterone directly
stimulates erythropoiesis, which partially explains the
higher hemoglobin concentration in men than in
women
ERYTHROPOIETIN
➢ EPO is a thermostable, nondialyzable, glycoprotein
hormone with a molecular weight of 34 kD.
➢ EPO is a true hormone, being produced at one
location (kidney) and acting at a distant location (bone
marrow).
➢ It is a growth factor (or cytokine) that initiates an
intracellular message to the developing erythroid
cells; this process is called signal transduction
➢ EPO had three major effects:
▪ Allowing early release of reticulocytes from the
bone marrow
▪ Preventing apoptotic cell death
▪ Reducing the time needed for cells to mature in
the bone marrow
WBC PRODUCTION
LEUKOPOIESIS
➢ The process of generating white blood cells
(LEUKOCYTES) from the pluripotent
HEMATOPOIESIS STEM CELLS of the BONE
MARROW. There are two significant pathways to
generate various types of leukocytes:
➢ MYELOPOIESIS, in which leukocytes in the blood are
derived from MYELOID STEM CELLS, and
➢ LYMPHOPOIESIS, in which leukocytes of the
lymphatic system (LYMPHOCYTES) are generated
from lymphoid stem cells.
➢ Factors that promote differentiation of the CFU-GEM
into neutrophils, monocytes, eosinophils, and
basophils include GM-CSF, G- CSF, macrophage
colony-stimulating factor (M-CSF), IL3, IL5, IL11, and
KIT ligand.
NEUTROPHIL DEVELOPMENT
➢ Neutrophil development occurs in the bone marrow,
neutrophils share a common progenitor with
monocytes and distinct from eosinophils and
basophils, known as the granulocyte monocyte
progenitor (GMP). The major cytokine responsible for
the stimulation of neutrophil production is granulocyte
colony stimulating factor, or G-CSF.
➢ There are three pools of developing neutrophils in the
bone marrow:
▪ The stem cell pool:
o Consists of HSCs that are capable of self-
renewal and differentiation
▪ The proliferation pool
o Consists of cells that are dividing and
includes common myeloid progenitors
(CMPs), CFUGEMMs, and Granulocyte-
monocyte progenitors
▪ The maturation pool
o Consisting of cells undergoing nuclear
maturation that form the marrow reserve and
available for release: metamyelocytes, band
neutrophils, and segmented neutrophils.
MYELOBLAST
➢ Myeloblasts make up 0% to 3% of the nucleated cells
and the bone marrow and measure 14 to 20 " m in
diameter. They are often subdivided into type I, type
II, and type III myeloblasts
➢ First recognizable cell that begin the process of
granulopoiesis
➢ Earliest microscopically recognizable neutrophil
precursor cell in the bone marrow
➢ Large euchromatic spherical nucleus with three to five
nucleoli
➢ Large nuclear to cytoplasmic volume
➢ The small amount of agranular cytoplasm stains
intensely basophilic
PROMYELOCYTE
➢ Comprise of 1% to 5% of the nucleated cells in the
bone marrow.
➢ They are relatively larger than the myeloblast cells
and measure 16 to 25" m in diameter.
➢ The nucleus is round to oval and is often eccentric
➢ Only cells to produce azurophilic granules
➢ Azurophilic (primary) granules in the cytoplasm
MYELOCYTES oxidants and
release cationic
➢ First that exhibit specific granules proteins
➢ Last stage capable of Mitosis Move in a zigzag Granules contain
➢ Recognition of the neutrophil, eosinophil, and basophil pattern in the major basic
lines is possible presence of protein
▪ NEUTROPHIL: patches of grainy pale pink chemoattractant
cytoplasm representing secondary granules Phagocytose a
begin to be evident in the area of the Golgi foreign particle
Apparatus. This has been referred to as the dawn Bactericidal
of neutrophilia activity mediated
▪ EOSINOPHIL: characterized by the presence of by H2O2
superoxide anion,
large, pale, reddish orange, secondary granules,
myeloperoxidase,
along with azure granules in blue cytoplasm. The
and free halogen
nucleus is similar to that described for neutrophil Important in the
myelocytes defense against
infectious agents
METAMYELOCYTE
Can cause tissue
➢ constitute 3% to 20% of nucleated marrow cells necrosis, tissue
➢ From this stage forward, the cells are no longer injury, and
inflammation
capable of division and the major morphologic change
is in the shape of the nucleus
➢ The nucleus is intended (kidney bean shaped or MONOCYTES
peanut shaped), and the chromatin is increasingly
➢ Appear to be larger than neutrophils (diameter of 15
clumped. Nucleoli are absent
to 20" m) because they tend to stick to and spread out
➢ Synthesis of tertiary granules (also known as
on glass or plastic
gelatinase granules) may begin during this stage
➢ Are slightly immature cells whole ultimate goal is to
➢ The size of the metamyelocyte is slightly smaller than
enter the tissues and mature into macrophages,
that of the myelocyte (14 to 16" m)
osteoclasts, or dendritic cells
➢ The cytoplasm contains very little residual ribonucleic
➢ The nucleus may be round, oval, or kidney shaped
acid (RNA) and therefore little to no basophilia
but more often is deeply indented (horseshoe shaped)
BAND (STAB) CELL or folded on itself
➢ The chromatin pattern is looser than in the other
➢ bands make up 9% to 32% of nucleated marrow cells leukocytes and has sometimes been described as
and 0% to 5% of the nucleated peripheral blood cells lace-like or stringy
➢ All evidence of RNA (cytoplasmic basophilia) is ➢ Their cytoplasm is blue-grey, with fine azure granules
absent, and tertiary granules continue to be formed often referred to as azure dust or a ground-glass
during this stage appearance
➢ Secretory granules (Secretory Vesicles) may begin to ➢ Monocytes remain in the circulation approximately 3
be formed during this stage days. Monocytes with different patterns of chemokine
➢ The nucleus is highly clumped, and the nuclear receptors have different target tissues and different
indentation that began in the metamyelocyte stage functions
now exceeds one half of the diameter of the nucleus, ➢ Mononuclear phagocyte system (reticuloendothelial
but actual segmentation has not yet occurred system)
➢ Defense against microorganism including
MATURE GRANULOCYTE mycobacteria, fungi, bacteria, protozoa, and viruses
➢ Called histocytes or macrophage when migrates to
➢ Segmented Neutrophils - make up 7% to 30% of
the tissue
nucleated cells in the bone marrow. Secretory
granules continue to be formed during this stage. The DIFFERENTIATION INTO MACROPHAGES
only morphologic difference between segmented In areas of inflammation or infection (inflammatory
neutrophils and bands is the presence of between two macrophages)
and five nuclear lobes connected by thread-like As "resident" macrophages in:
filaments ➢ Liver (Kupffer Cells)
➢ Mature Eosinophils - usually display a bilobed ➢ Lungs (Alveolar Macrophages)
nucleus. Their cytoplasm contains characteristic ➢ Brain (Microglia)
refractile, orange-red secondary granules ➢ Skin (Langerhans Cells)
➢ Spleen (Splenic Macrophages)
NEUTROPHILS EOSINOPHILS BASOPHILS ➢ Intestines (Intestinal Macrophages)
Phagocytosis Modulate Immediate ➢ Peritoneum (Peritoneal Macrophages)
Inflammatory Hypersensitivity ➢ Bone (Osteoclasts)
Response Reactions ➢ Synovial Macrophages (Type A Cells)
Bacterial Activity Anthelmintic ➢ Kidneys (Renal Macrophages)
activity - ➢ Reproductive Organ Macrophages
generating ➢ Lymph Nodes (Dendritic Cells)
LYMPHOCYTES ➢ Megakaryocyte progenitors arise from the common
myeloid progenitor under the influence of the
➢ Lymphocytes are divided into three major groups: T transcription gene product, GATA-1, regulated by
Cells, B Cells, and Natural Killer (NK) Cells cofactor FOG1
▪ T and B Cells are major players in adaptive ➢ Megakaryocyte differentiation is suppressed by
immunity another transcription gene product, MYB, so GATA-1
▪ NK Cells make up small percentage of act in opposition to balance megacaryocytopoiesis
lymphocytes and are part of innate immunity ➢ Three megakaryocyte lineage-committed progenitor
➢ Lymphocytes can be subdivided into two major stages, defined by their in vitro culture colony
categories: Those that participate in humoral immunity characteristics, arise from the common myeloid
by producing antibodies and those that participate in progenitor
cellular immunity by attacking foreign organisms or ➢ In order of differentiation these are:
cells directly ▪ The least mature burst-forming unit (BFU-Meg)
➢ Antibody producing lymphocytes are called B ▪ The intermediate colony forming unit (CFU-Meg)
lymphocytes or simply B cells because they develop ▪ The more mature progenitor, the light-density
in the bone marrow CFU (LD-CFU-Meg)
➢ Cellular immunity is accomplished by two types of ▪ All three progenitor stages resemble lymphocytes
lymphocytes: T cells, so named because they develop and cannot be distinguished by Writghtstained
in the thymus, and NK cells, which develop in both the light microscopy
bone marrow and the thymus
➢ NK lymphocytes function as part of innate immunity
and are capable of killing certain tumor cells and
virus-infected cells without prior sensitization
➢ In addition, NK cells modulate the functions of other
cells, including macrophages and T cells
➢ Lymphocytes are different from the other leukocytes
in several ways, including the following:
▪ Lymphocytes are not end cells. They are resting
cells, and when stimulated, they undergo mitosis
to produce both memory and effector cells
▪ Unlike other leukocytes, lymphocytes recirculate
from the blood to the tissues and back to the
blood
▪ B and T lymphocytes are capable of rearranging
antigen receptor gene segments to produce a
wide variety of antibodies and surface receptors
▪ Although early lymphocyte progenitors such as
the common lymphoid progenitor originate in the
bone marrow, T and NK lymphocytes develop THROMBOCYTOPOIESIS (Platelet Shedding)
and mature outside the bone marrow
➢ Illustrate the process of platelet Shedding, termed
T CELLS B CELLS thrombocytopoiesis. During thrombocytopoiesis a
➢ Cells mediated ➢ Humoral Immunity single megakaryocyte may shed 2000 to 4000
immunity ➢ Plasma cells and platelets
➢ Delayed Produce antibodies ➢ The total platelet population turns over in 8 to 9 days
hypersensitivity ➢ Minor populations (the so-called platelet life span)
➢ Graft rejection (10-20% of
➢ Graft vs Host lymphocytes)
Disease ➢ Short life span
➢ Defense against
intracellular
organisms (tubercle
bacilli & brucella)
➢ Life Span: Months
to Years

MEGAKARYOPOIESIS

➢ is the process by which megakaryocytes and

ultimately platelets develop
➢ Earlier influences include GM-CSF, IL-6, IL-11, KIT
ligand, and TPO. The stimulating hormonal factor
TPO (also known as MPL ligand), along with IL-11,
controls the production and release of platelets. The
liver is the main site of production of TPO.