Hemopoiesis

Josiah Bimabam
BMLS (Buea) MMLSc (Calabar)
St Louis Higher Institute of Medical Studies Douala
 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
increasingly restricted to components of the axial
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skeleton.
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Figure 13-1 Copyright © McGraw-Hill Companies
 Stem Cells, Growth Factors,
& Differentiation
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.

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 Hemopoietic Stem Cells
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.
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Figure 13-2 Copyright © McGraw-Hill Companies
 Progenitor & Precursor Cells
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 types
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 Progenitor & Precursor Cells
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
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large numbers
Hemopoiesis, Josiah Bimabam,of differentiated,
St Louis University mature cells.
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Figure 13-3 Copyright © McGraw-Hill Companies
 Progenitor & Precursor Cells
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.

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 Hemopoiesis, Josiah Bimabam, St Louis University
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 Bone Marrow
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.
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 Bone Marrow
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.

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 Bone Marrow
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.

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Figure 13-4 Copyright © McGraw-Hill Companies
Figure 13-5 Copyright © McGraw-Hill Companies
 Medical Application
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
results with animal models are promising.

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 Maturation of Erythrocytes
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 disappear.
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 Maturation of Erythrocytes
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.
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Figure 13-6 Copyright © McGraw-Hill Companies
Figure 13-7 Copyright © McGraw-Hill Companies
 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 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.

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 The most
immatur
e cell

Figure 13-8 Copyright © McGraw-Hill Companies

 Medical Application
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.

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 Maturation of Granulocytes
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.

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Figure 13-12 Copyright © McGraw-Hill Companies
 Maturation of Granulocytes
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 appear in the bloodstream.

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 Maturation of Agranulocytes
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.

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 Maturation of Agranulocytes
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.
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 Medical Application
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.
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 Origin of Platelets
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.
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Figure 13-13 Copyright © McGraw-Hill Companies
 Origin of Platelets
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
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Figure 13-13 Copyright © McGraw-Hill Companies
Figure 13-13 Copyright © McGraw-Hill Companies
Figure 13-5 Copyright © McGraw-Hill Companies
 Origin of Platelets
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.

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 Origin of Platelets
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
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and is removed by
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macrophages.
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Figure 13-14 Copyright © McGraw-Hill Companies
 Origin of Platelets
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
Hemopoiesis, Josiah Bimabam, St Louis University
and is removed by
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macrophages.
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 CASE STUDY
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 10 12/L
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 Questions
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
patient?
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 Answer to Question 1
When the blood is not well oxygenated, the bone
marrow responds by producing more red blood cells to
carry more oxygen.

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 Answer to Question 2
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
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 Answer to Question 3
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.

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 Thank You

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