IUC_Haematology_ Lecture 2_Hemopoiesis-2021 - Copy.pptx

Josiah Bimabam
BMLS (Buea) MMLSc (Calabar)
St Louis Higher Institute of Medical
Studies Douala
Hemopoiesis

Hemopoiesis
 Hemopoiesis (or hematopoiesis) is the
process of blood cell formation aiming at
continual replacement of short-lived mature
blood cells
 It first occurs in a mesodermal cell population
of the embryonic yolk sac, and shifts during
the second trimester mainly to the developing
liver, before becoming concentrated in newly
formed bones during the last 2 months of
gestation.
 Hemopoietic bone marrow occurs in many
locations through puberty, but then becomes
2
Hemopoiesis, Josiah Bimabam, St Louis
University Institute/IUC

Copyright © McGraw-Hill Companies
Figure 13-1

Stem Cells, Growth Factors,
& Differentiation
4
 Stem cells are pluripotent cells capable of
asymmetric division and self-renewal.
 Some of their daughter cells form specific,
irreversibly differentiated cell types, and other
daughter cells remain as a small pool of
slowly dividing stem cells.
 All blood cells arise from a single major type
of pluripotent stem cell in the bone marrow
that can give rise to all the blood cell types.

Hemopoietic Stem Cells
5
 Hemopoietic pluripotent stem cells are rare, but they
proliferate and form two major lineages of progenitor
cells with restricted potentials (committed to produce
specific blood cells):
1. One for lymphoid cells (lymphocytes).
2. Another for myeloid cells (Gr. myelos, marrow) that
develop in bone marrow.
 Myeloid cells include granulocytes, monocytes,
erythrocytes, and megakaryocytes.
 The lymphoid progenitor cells migrate from the
bone marrow to the thymus or the lymph nodes,
spleen, and other lymphoid structures, where they
proliferate and differentiate.

Figure 13-2

Progenitor & Precursor Cells
7
 The progenitor cells for blood cells are commonly
called colony-forming units (CFUs), because
they give rise to colonies of only one cell type
when cultured or injected into a spleen.
 There are four major types of progenitor
cells/CFUs:
1. Erythroid lineage of CFU-erythrocytes (CFU-E).
2. Thombocytic lineage of CFU-megakaryocytes
(CFU-Meg).
3. Granulocyte-monocyte lineage of CFU-
granulocytes-monocytes (CFU-GM).
4. Lymphoid lineage of CFU-lymphocytes of all

8
 Each progenitor cell produces precursor cells
(or blasts) that gradually assume the
morphologic characteristics of the mature,
functional cell types they will become.
 In contrast, stem and progenitor cells cannot be
morphologically distinguished and simply
resemble large lymphocytes.
 While stem cells divide at a rate only sufficient to
maintain their relatively small population,
progenitor and precursor cells divide more rapidly,
producing large numbers of differentiated, mature
cells.

Figure 13-3

10
 Progenitor cells, committed to forming each type
of mature blood cell, proliferate and differentiate
within microenvironmental niches of stromal cells,
other cells, and ECM with specific growth factors.
 Hemopoietic growth factors, often called colony-
stimulating factors (CSF) or cytokines, are
glycoproteins that stimulate proliferation of
progenitor and precursor cells and promote cell
differentiation and maturation within specific
lineages.

11

Bone Marrow
12
 Bone marrow is found in the medullary canals of long
bones and in the small cavities of cancellous bone,
with two types based on their appearance at gross
examination:
1. Blood-forming red bone marrow, whose color is
produced by an abundance of blood and
hemopoietic cells.
2. Yellow bone marrow, which is filled with adipocytes
that exclude most hemopoietic cells.
 In the newborn all bone marrow is red and active in
blood cell production, but as the child grows, most of
the marrow changes gradually to the yellow variety.
 Under certain conditions, such as severe bleeding or
hypoxia, yellow marrow reverts to red.

Bone Marrow
13
 Red bone marrow contains a reticular connective
tissue stroma, hemopoietic cords or islands of cells,
and sinusoidal capillaries.
 The stroma is a meshwork of specialized fibroblastic
cells called stromal cells (also called reticular or
adventitial cells) and a delicate web of reticular fibers
supporting the hemopoietic cells and macrophages.
 The matrix of bone marrow also contains collagen
type I, proteoglycans, fibronectin, and laminin, the
latter glycoproteins
interacting with integrins to bind cells to the matrix.
 Red marrow is also a site where older, defective
erythrocytes undergo phagocytosis by macrophages,
which then reprocess heme-bound iron for delivery to
the differentiating erythrocytes.

Bone Marrow
14
 The hematopoietic niche in marrow includes the
stroma,
osteoblasts, and megakaryocytes.
 Between the hematopoietic cords run the
sinusoids, which have discontinuous
endothelium, through which newly differentiated
blood cells and platelets enter the circulation.

Figure 13-4

Figure 13-5

Medical Application
17
 Red bone marrow also contains stem cells that can
produce other tissues in addition to blood cells.
 These pluripotent cells may make it possible to
generate specialized cells that are not rejected by the
body because they are
produced from stem cells from the marrow of the
same patient.
 The procedure is to collect bone marrow stem cells,
cultivate them in appropriate medium for their
differentiation to the cell type needed for transplant,
and then use the resulting cells to replace defective
cells.
 These studies in regenerative medicine are at early
stages, but

Maturation of Erythrocytes
18
 Several major changes take place during
erythropoiesis:
1. Cell and nuclear volumes decrease.
2. The nucleoli diminish in size and disappear.
3. Chromatin density increases until the nucleus
presents a pyknotic appearance and is finally
extruded from the cell.
4. There is a gradual decrease in the number of
polyribosomes (basophilia), with a simultaneous
increase in the amount of hemoglobin (a highly
eosinophilic protein).
5. Mitochondria and other organelles gradually

Maturation of Erythrocytes
19
 There are three to five intervening cell divisions
between the proerythroblast and the mature
erythrocyte.
 The development of an erythrocyte from
proerythroblast to the release of reticulocytes into the
blood takes approximately 1 week.
 The glycoprotein erythropoietin, a growth factor
produced by cells in the kidneys, stimulates
production of mRNA for globins, the protein
components of hemoglobin, and is essential for the
production of erythrocytes.
 Reticulocytes pass to the circulation (where they may
constitute 1% of the red blood cells), quickly lose the
polyribosomes, and mature as erythrocytes.

Figure 13-6

Figure 13-7

Maturation of Granulocytes
22
 Granulopoiesis involves cytoplasmic changes
dominated by
synthesis of proteins for the azurophilic granules
and specific granules.
 These proteins are produced in the rough ER and
Golgi apparatus in two successive stages:
1. Made initially are the azurophilic granules,
which contain lysosomal hydrolases, stain with
basic dyes, and are basically similar in all three
types of granulocytes.
2. Golgi activity then changes to produce proteins
for the specific granules, whose contents differ
in each of the three types of granulocytes.

Figure 13-8
The
most
immatur
e cell

Medical Application
24
 Before its complete maturation, the neutrophilic
granulocyte passes through an intermediate
stage, the band cell (or stab cell), in which the
nucleus is elongated but not yet polymorphic.
 The appearance of large numbers of immature
neutrophils
(band cells) in the blood, sometimes called a
“shift to the
left,” is clinically significant, usually indicating a
bacterial
infection.

25
 The vast majority of granulocytes are neutrophils and the
total time required for a myeloblast to produce mature,
circulating neutrophils ranges from 10 to 14 days.
 Developing and mature neutrophils exist in four
functionally and anatomically defined compartments:
1. The granulopoietic compartment in active marrow.
2. Storage as mature cells in marrow until release.
3. The circulating population.
4. A population undergoing margination, a process in which
neutrophils adhere loosely and accumulate transiently
along the endothelial surface in venules and small veins.
Margination can persist for several hours and is not
always followed by emigration from the vessels.
5. Inflamed connective tissue.

Figure 13-12

27
 Neutrophilia, an increase in the number of circulating
neutrophils, does not necessarily imply an increase in
granulopoiesis.
1. Transitory neutrophilia:
 Intense muscular activity or the administration of epinephrine
can cause the marginating neutrophils to move into the
circulating compartment.
 Glucocorticoids increase the mitotic activity of neutrophil
precursors.
 Transitory neutrophilia is typically followed by a recovery
period during which no neutrophils are released.
2. Prolonged neutrophilia:
 Bacterial infections is due to an increase in production of
neutrophils and a shorter duration of these cells in the
medullary storage compartment.
 In such cases, immature forms such as band or stab cells,
neutrophilic metamyelocytes, and even myelocytes may

Maturation of Agranulocytes
28
 The precursor cells of
monocytes & lymphocytes do
not show specific
cytoplasmic granules or
nuclear lobulation.
 The monoblast is a
committed progenitor cell
that is virtually identical to the
myeloblast morphologically.
 Promonocytes divide twice
as they develop into
monocytes.
 Monocytes circulate in blood
for several hours and enter
tissues where they mature as
macrophages & function for
up to several months.

Maturation of Agranulocytes
29
 The first identifiable
progenitor of lymphoid
cells is the lymphoblast, a
large cell capable of
dividing two or three times
to form lymphocytes.
 In the bone marrow and in
the thymus, these cells
synthesize the specific cell
surface proteins that
characterize B or T
lymphocytes,
respectively.

Medical Application
30
 Abnormal proliferation of stem cells in bone marrow can
produce a range of myeloproliferative disorders.
 Leukemias are malignant clones of leukocyte precursors.
 They can occur in both lymphoid tissue (lymphoblastic
leukemias) and bone marrow (myelogenous leukemias).
 In these diseases, there is usually a release of large
numbers of immature cells into the blood and an overall
shift in hemopoiesis, with a lack of some cell types and
excessive production of others.
 The patient is usually anemic and prone to infection.
 Diagnosis of leukemias and other bone marrow
disturbances involves bone marrow aspiration. A needle is
introduced through the compact bone, typically at the iliac
crest, and a sample of marrow is withdrawn.
 Immunocytochemistry with labeled monoclonal antibodies
specific to membrane proteins of precursor blood cells
contributes to a more precise diagnosis of the leukemia.

Origin of Platelets
31
 Platelets originate in the red bone marrow by
dissociating from mature megakaryocytes, which in
turn differentiate from megakaryoblasts in a process
driven by thrombopoietin.
 The megakaryoblast is 25 to 50 μm in diameter and
has a large ovoid or kidney-shaped nucleus, often
with several small nucleoli.
 Before differentiating, these cells undergo
endomitosis, with repeated rounds of DNA replication
not separated by cell divisions, resulting in a nucleus
that is highly polyploid (i.e, 64N or >30 times more
DNA than in a normal diploid cell).
 The cytoplasm of this cell is homogeneous and highly
basophilic.

Figure 13-13

Origin of Platelets
33
 Megakaryocytes are giant cells, up to 150 μm in
diameter, with large, irregularly lobulated polyploid
nuclei, coarse chromatin, and no visible nucleoli.
 Their cytoplasm contains numerous mitochondria, a
well-developed RER, and an extensive Golgi
apparatus from which arise the conspicuous specific
granules of platelets.
 They are widely scattered in marrow, typically near
sinusoidal capillaries.
 To form platelets, megakaryocytes extend several
long(>100 μm), wide (2-4 μm) branching processes
called proplatelets.
 These cellular extensions penetrate the sinusoidal
endothelium and are exposed in the circulating blood
of the sinusoids

Origin of Platelets
37
 Internally proplatelets have a framework of
actin filaments and microtubules along which
membrane vesicles and specific granules are
transported.
 A loop of microtubules forms a teardrop-
shaped enlargement at the distal end of the
proplatelet, and cytoplasm within these loops
is pinched off to form platelets with their
characteristic marginal bundles of
microtubules, vesicles, and granules.

Origin of Platelets
38
 Mature megakaryocytes have numerous
invaginations of plasma membrane ramifying
throughout the cytoplasm, called demarcation
membranes, which were formerly considered
“fracture lines” or “perforations” for the release
of platelets but are now thought to represent a
membrane reservoir that facilitates the
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.

Figure 13-14

Origin of Platelets
40
 Mature megakaryocytes have numerous
invaginations of plasma membrane ramifying
throughout the cytoplasm, called demarcation
membranes, which were formerly considered
“fracture lines” or “perforations” for the release
of platelets but are now thought to represent a
membrane reservoir that facilitates the
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.

CASE STUDY
41
 A 42-year-old premenopausal woman has
emphysema. This lung disease impairs the ability
to oxygenate the blood, so patients experience
significant fatigue and shortness of breath.
 To alleviate these symptoms, oxygen is typically
prescribed, and this patient has a portable
oxygen tank she carries with her at all times,
breathing through nasal cannulae.
 Before she began using oxygen, her red blood
cell (RBC) count was 5.8 x 1012/L. After oxygen
therapy for several months, her RBC count
dropped to 5.0 x 1012/L

Questions
42
1. What physiologic response
explains the elevation of the first
RBC count?
2. What hormone is responsible?
How is its production stimulated?
What is the major way in which it
acts?
3. What explains the decline in RBC
count with oxygen therapy for this

Answer to Question 1
43
 When the blood is not well oxygenated, the bone
marrow responds by producing more red blood
cells to carry more oxygen.

44
 The hormone that stimulates RBC production is
erythropoietin (EPO). The peritubular cells of the
kidney detect hypoxia.
 A hypoxia-sensitive transcription factor is
produced that moves to the peritubular cell
nucleus and upregulates transcription of the EPO
gene.
 EPO acts by preventing apoptosis of the erythroid
colony-forming unit. In RBC precursors, it also
shortens the cell cycle time between mitoses and
reduces the number of mitotic divisions; and it
promotes early release of reticulocytes from the
bone marrow

45
 Once the patient was receiving oxygen
therapy, hypoxia diminished and EPO
production also declined.
 Thus, production of new RBCs slowed.
At the same time, RBCs reaching 120
days of age were removed from the
circulation. Thus the total number of
circulating RBCs decreased.

46

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