Hematopoiesis by Deacon Siyum Alebachew

1. Hemopoiesis
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2. Hemopoiesis
Yekatit
Y12 Hospital Medical College
By:- Siyum Alebachew Mekonen
ID:- Y12HMCUR/055/14
Addis Ababa Ethiopia
March 8, 2022
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3.  Hemopoiesis is the process of blood cell formation
 Mature blood cells have a relatively short life span and
must be continuously replaced with stem cell progeny
produced in the hemopoietic organs.
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Blood Cell Type Life Span
RBC ≈ 120 days
Platelets ≈ 10 days
Neutrophil Few days in CT
Monocyte Circulate for ≈ 8 hrs then enter to
tissue to function for several months
Lymphocyte Few days to many years

4. Fetal Hematpoiesis
 3 phases:
Mesoblastic- blood island
Hepatic- liver and spleen
Myeloid- bone marrow
 Tissues producing blood cells
 Lymphoid
 Spleen and lymph nodes (produces lymphocytes)
 Myeloid
 Red bone marrow: (produces RBC, WBC, and
platelets)
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5.  Blood cells arise from the (hemopoiesis occurs )
Yolk sac: in the earliest phase of human
embryogenesis
Liver (primarily): in the second trimester with
the spleen also playing a role
Bone marrow: in the third trimester (major
hematopoietic organ)
 Infants: bone marrow, practically all bones
 Adults: vertebrae, ribs, sternum, sacrum and
Ilium, proximal ends of femur
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6.  Before reaching maturity and being released into
the circulation, blood cells go through specific
stages of differentiation and maturation.
 Because these processes are continuous, cells with
characteristics that lie between the various stages
are frequently encountered in smears of blood or
bone marrow.
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7. Stem Cells, Growth Factors & Differentiation
 Stem cells are pluripotent cells capable of
asymmetric division and self-renewal.
 Their daughter cells form:
specific, irreversibly differentiated cell types &
remain stem cells
 A constant number of pluripotent stem cells is
maintained in a pool and cells recruited for
differentiation are replaced with daughter cells
from the pool.
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8. Pluripotent Hemopoietic Stem Cells
 It is believed that all blood cells arise from a single type of
stem cell in the bone marrow called a pluripotent stem
cell because it can produce all blood cell types.
 The pluripotent stem cells proliferate and form two major
cell lineages:
♣ Myeloid cells that develop in bone marrow in to
granulocytes, monocytes, erythrocytes, and
megakaryocytes.
♣ Lymphoid cells (lymphocytes): Early in their
development, lymphoid cells migrate from the bone
marrow to the thymus or to the lymph nodes, spleen,
and other lymphoid structures, where they proliferate
and differentiate
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9. Progenitor & Precursor Cells
 The pluripotent stem cells give rise to daughter cells
with restricted potentials called progenitor cells or
colony-forming units (CFUs), since they give rise to
colonies of only one cell type.
 There are four types of progenitors/CFUs:
♠ Erythroid lineage of CFU-erythrocytes (CFU-E)
♠ Thrombocytic lineage of CFU-megakaryocytes (CFU-
Meg)
♠ Granulocyte-monocyte lineage of CFU-granulocytes-
monocytes (CFU-GM)
♠ Lymphoid lineage of CFU-lymphocytes of all types
(CFU-L).
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10.  All four progenitor/CFUs produce precursor cells
or blasts in which the cells' morphologic
characteristics begin to differentiate, suggesting
the mature cell types they will become
 In contrast, stem and progenitor cells cannot be
morphologically distinguished and resemble large
lymphocytes.
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11. 3/8/2022 11
Pluripotent stem cell
Progenitor (CFU)
Precursor (blast)
Growth factors

12.  Hemopoiesis depends on favorable
microenvironmental conditions and the presence of
paracrine or endocrine growth factors.
 This microenvironment in hematopoietic organs is
furnished largely by stromal cells and their
extracellular matrix (ECM), which together create
the niche in which stem cells are maintained.
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13.  Hemopoietic growth factors, called colony-
stimulating factors (CSF) or hematopoietins
(poietins), are proteins with complex, overlapping
functions in:
♠ stimulating proliferation (mitogenic activity) of
immature (mostly progenitor and precursor) cells
♠ supporting differentiation of maturing cells
♠ enhancing the functions of mature cells
 These three functions may all occur in the same
growth factor or they may be expressed with different
levels of intensity in different growth factors.
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14. Bone Marrow / Medulla Osseium
 It is found in:
 Medullary or marrow cavity of long bones
 Epiphyseal region of long, short, flat & irregular bones
 Spaces between the bony spicules (trabeculae) of the
spongiosa
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15.  Two types of bone marrow
 Red marrow
 Hematopoiteic marrow
 Found in all bones of fetal to childhood
 Weighs about 1.3 kg but only 400gm is capable of
RBC formation
 Diminish in adults
 Yellow marrow
 Found in the medullary cavity of adults
 Increase as age increases
 Form blood cells in cases of emergency
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16.  Red bone marrow looks like blood but with a thicker
consistency which is composed of:
♦ Stroma: is a meshwork of specialized fibroblastic
cells called reticular or adventitial cells and a
delicate web of reticular fibers supporting
hemopoietic cells, adipocytes & macrophages.
♦ Hemopoietic cords or islands of cells
♦ Sinusoidal capillaries
 The matrix of bone marrow also contains collagen type
I, proteoglycans, fibronectin, and laminin
 Laminin interacting with integrins bind cells to the
matrix.
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Red Bone Marrow

17. Red Bone Marrow
 Reticular cells secrete various colony-stimulating
factors and the stroma forms the
microenvironment for hemopoietic stem cell
maintenance, proliferation and differentiation.
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18. Red Bone Marrow Stroma
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Stromal Cells
• Adipocytes
• Fibroblast
• Reticulum cella
• Endothelial cells
• Macrophages
Extracellular Molecules
• Collagen type I
• Glycoprotein (fibronectin,
laminin)
• Glycosaminoglycans
(hyaluronic acid &
chondroitin derivates)
• Growth factors  for cell
survival
Secrete

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Red Bone Marrow

20.  A mature cell is one that has differentiated to the
stage at which it can carry out all its specific
functions.
 Erythrocyte maturation involves:
♣ hemoglobin synthesis
♣ formation of a small, enucleated, biconcave
corpuscle
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Maturation of Erythrocytes

21. Stages of RBC Formation (Erythropoiesis)
Hemocytoblast
Proerythroblast/Rubriblast
Basophilic Erythroblast
Polychromatophilic Erythroblast
Orthochromatophilic/Acidophylic Erythroblast
Reticulocyte
Erythrocyte
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22.  The major changes that take place during erythrocyte
maturation include:
◙ Cell and nuclear volume decrease
◙ Nucleoli diminish in size and disappear
◙ Chromatin becomes increasingly denser until the
nucleus presents a pyknotic appearance and is finally
extruded from the cell
◙ Gradual decrease in the number of polyribosomes
(basophilia decreases)
◙ Simultaneous increase in the amount of hemoglobin (an
acidophilic protein) within the cytoplasm
◙ Mitochondria and other organelles gradually disappear.
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23.  There are three to five intervening cell divisions
between the proerythroblast and the mature
erythrocyte.
 The development of an erythrocyte from the first
recognizable cell of the series to the release of
reticulocytes into the blood takes approximately a
week.
 The glycoprotein erythropoietin (Epo), a growth factor
produced in the kidneys, stimulates production of
mRNA for globin, the protein component of
hemoglobin and is essential for the production of
erythrocytes.
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24.  Cells in the erythroid series include:
a. Proerythroblast
 first recognizable cell in the erythroid series
 large cell with loose, lacy chromatin, nucleoli,
and basophilic cytoplasm
b. Basophilic erythroblast
 more strongly basophilic cytoplasm
 condensed nucleus with no visible nucleolus.
NB: The basophilia of these two cell types is caused
by the large number of polyribosomes synthesizing
hemoglobin
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25. c. Polychromatophilic erythroblast
 cell volume is reduced
 polyribosomes decrease
 some cytoplasmic areas begin to be filled with
hemoglobin, producing regions of both basophilia
and acidophilia in the cell
d. Orthochromatophilic erythroblast
 cell and nuclear volumes continue to condense
 no basophilia is evident, resulting in a uniformly
acidophilic cytoplasm
 late in this stage, this cell ejects its nucleus which is
phagocytosed by macrophages
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26. e. Reticulocyte
 the cell still has a small number of polyribosomes
that, when treated with the dye brilliant cresyl blue,
form a faintly stained network
 reticulocytes pass to the circulation, where they
may constitute 1% of the red blood cells
 lose the polyribosomes and quickly mature as
erythrocytes
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27. Maturation of Erythrocytes
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28. Erythropoiesis
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29. Erythropoiesis
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30. Maturation of Granulocytes
 Granulopoiesis: involves cytoplasmic changes
dominated by synthesis of proteins for the
azurophilic granules and specific granules
 These proteins are produced in the rER and the
prominent Golgi apparatus in two successive stages
 Azurophilic granules
◙ contain lysosomal hydrolases
◙ stain with basic dyes
◙ somewhat similar in all three types of
granulocytes
◙ they are made first
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31.  Golgi activity then changes to produce proteins for
the specific granules, whose contents differ in each
of the three types of granulocytes and endow each
type with certain different properties.
 In sections of bone marrow, cords of
granulopoietic cells can be distinguished by
their granule-filled cytoplasm from
erythropoietic cords
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32. Stages of granulopoiesis
a. Myeloblast
 It is the most immature recognizable cell in the
myeloid series
 It has a finely dispersed chromatin, and faint
nucleoli.
b. Promyelocyte
 It is characterized by its basophilic cytoplasm
and azurophilic granules containing
lysosomal enzymes and myeloperoxidase.
 Different promyelocytes activate different sets of
genes, resulting in lineages for the three types of
granulocytes.
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33. c. Myelocytes
 The first visible sign of differentiation appears in this
stage
 Specific granules gradually increase in number
d. Metamyelocytes
 Most of the cytoplasm eventually occupied by specific
granules
 neutrophilic, basophilic & eosinophilic metamyelocytes
mature with further condensations of the nuclei.
 Before its complete maturation the neutrophilic
granulocyte passes through an intermediate stage, the stab
or band cell, in which its nucleus is elongated but not yet
polymorphic.
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34. Maturation of Granulocytes
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Band (stab) cell
about 11 days

35. Developing Erythrocytes & Granulocytes in
Marrow
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36. Granulopoiesis: Major Granulocyte Precursors
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37. Leukopoiesis
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38. Hematopoiesis
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39. …
 The total time taken for a myeloblast to emerge as
a mature, circulating neutrophil is about 11 days.
 Under normal circumstances, five mitotic
divisions occur in the myeloblast, promyelocyte,
and neutrophilic myelocyte stages.
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40.  Developing and mature neutrophils can be
considered to exist in four functionally and
anatomically defined compartments:
1. Granulopoietic compartment in marrow
2. Storage as mature cells in marrow until release
3. Circulating population
4. Marginating population of cells adhering to
endothelial cells of postcapillary venules and
small veins
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41.  Neutrophils and other granulocytes enter the connective
tissues by migrating through intercellular junctions
between endothelial cells of postcapillary venules in
diapedesis.
 The connective tissues thus form a fifth terminal
compartment for neutrophils, where the cells reside for a
few days and then die by apoptosis, regardless of whether
they have performed their major function of phagocytosis.
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42. Functional Compartments of Neutrophils
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CT
Neutrophilia

43. Maturation of Agranulocytes
 Study of the precursor cells of monocytes and
lymphocytes is difficult, because these cells do not
show specific cytoplasmic granules or nuclear
lobulation, both of which facilitate the
distinction between young and mature forms of
granulocytes.
 Monocytes and lymphocytes in smear preparations
are discriminated mainly on the basis of size,
chromatin structure, and the presence of
nucleoli.
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44. Comparison of Agranulocyte
Characteristics Monocyte Lymphocyte
Size Large ≈ 18um in
diameter early
Small
Chromatin
structure
Lace like Condensed
Nucleoli Visible Less visible
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45. Monocyte
a. Monoblast
 It is a committed progenitor cell that is virtually
identical to the myeloblast in its morphologic
characteristics.
b. Promonocyte
◙ Large cell (up to 18um in diameter)
◙ Has basophilic cytoplasm
◙ Has large, slightly indented nucleus
◙ Chromatin is lacy
◙ Nucleoli are evident.
◙ Promonocytes divide twice as they develop into
monocytes.
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46. c. Monocyte
 A large amount of rER and an extensive Golgi
apparatus present in which granule
condensation occurs
 These granules are primary lysosomes, which
are observed as fine azurophilic granules in
blood monocytes
 Mature monocytes enter the bloodstream,
circulate for about eight hours, and then enter
tissues where they mature as macrophages (or
other phagocytic cells) and function for several
months
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Monoblast
Promonocyte
Monocyte
Macrophage

48. Lymphocytes
 All lymphocyte progenitor cells originate in the
bone marrow.
 Some of these lymphocytes migrate to the thymus,
where they acquire the full attributes of T
lymphocytes.
 Subsequently, T lymphocytes populate specific
regions of peripheral lymphoid organs.
 Other bone marrow lymphocytes differentiate into
B lymphocytes in the bone marrow and then
migrate to peripheral lymphoid organs, where they
inhabit and multiply in their own special
compartments
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49.  As lymphocytes mature:
their chromatin becomes more compact
nucleoli become less visible
cells decrease in size
 In addition, subsets of the lymphocyte series
acquire distinctive cell-surface receptors during
differentiation that can be detected by
immunocytochemical techniques
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50. a. Lymphoblast
 First identifiable progenitor of lymphoid
cells
 A large cell capable of dividing two or
three times to form prolymphocytes.
b. Prolymphocytes
 They are smaller and have relatively more
condensed chromatin
 Do not have the cell-surface antigens that
mark T or B lymphocytes.
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51.  In the bone marrow and in the thymus, these cells
synthesize cell-surface receptors characteristic of
the B or T lymphocyte lineages.
 In routine histological procedures B and T
lymphocytes cannot be distinguished;
immunocytochemical techniques using cell-
specific markers are required to make the
distinction.
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52. Origin of Platelets
 In adults, the membrane-enclosed cell fragments called
platelets originate in the red bone marrow by dissociating
from mature megakaryocytes, which in turn differentiate
from megakaryoblasts in a process driven by
thrombopoietin.
 Megakaryoblast
◊ It is 25–50 um in diameter
◊ Has a large ovoid or kidney-shaped nucleus with
numerous small nucleoli.
◊ Before differentiating, these cells undergo endomitosis,
with repeated rounds of DNA replication not separated by
cell divisions
◊ The cytoplasm is homogeneous & intensely basophilic
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53.  Megakaryocytes
◊ They are giant cells, 35–150 um in diameter
◊ Has irregularly lobulated polyploid nuclei
◊ Coarse chromatin, and no visible nucleoli
◊ Their cytoplasm contains numerous
mitochondria, a well-developed rER, & an
extensive Golgi apparatus from which arise
the conspicuous specific granules of platelets
◊ They are widely scattered in marrow, typically
near sinusoidal capillaries.
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54. Megakaryoblast & Megakaryocytes
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Endomitosis

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Megakaryoblasts
Promegakaryocytes
Megakaryocytes
Platelet
Origin of Platelets

56.  To form platelets, megakaryocytes extend several
long (>100 um), wide (2–4 um), branching
processes called proplatelets.
 These extending proplatelets penetrate the
sinusoidal endothelium and appear as long
processes disposed lengthwise with the blood flow
in these vessels
 The proplatelet framework consists of actin
filaments and a loose bundle of microtubules.
 the proplatelet has a teardrop-shaped enlargement
at the distal end. these loops is pinched off to form
platelets
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57. Platelet Formation
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58.  Mature megakaryocytes have numerous
invaginations of plasma membrane ramifying
throughout the cytoplasm, called demarcation
membranes which were formerly considered
"fracture lines" or "perforations" for release of
platelets, but are now thought to represent a
membrane reservoir that facilitates continuous
rapid proplatelet elongation.
 Each megakaryocyte produces a few thousand
platelets, after which the remainder of the cell
shows apoptotic changes and is removed by
macrophages.
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59. Stages Of Platelet Formation
HEMOCYTOBLAST
MEGAKARYOBLAST
MEGAKARYOCYTE
MEGAKARYOCYTE BREAK UP
PROPLATELETS
PLATELETS
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