MD MSc Anatomy Faculty of Medicine Islamic UniversityGaza Feb 2016 Hemopoiesis Hemopoiesis Hemopoiesis or hematopoiesis is the process of blood cell formation aiming at continual replacement of shortlived mature blood cells ID: 927403
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Slide1
Dr. Emad I H ShaqouraM.D, M.Sc. AnatomyFaculty of Medicine, Islamic University-GazaFeb., 2016
Hemopoiesis
Slide2HemopoiesisHemopoiesis (or hematopoiesis) is the process of blood cell formation aiming at continual replacement of short-lived mature blood cellsIt 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 skeleton.
Hemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016
2
Slide3Figure 13-1
Slide4Stem Cells, Growth Factors,& DifferentiationHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016
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.
Slide5Hemopoietic Stem CellsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016
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):
One for lymphoid cells (lymphocytes).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
dif
f
erentiate.
Slide6Figure 13-2
Slide7Progenitor & Precursor CellsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016
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:
Erythroid lineage of CFU-erythrocytes (CFU-E).Thombocytic 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
).
Slide8Progenitor & Precursor CellsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 20168
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.
Slide9Figure 13-3
Slide10Progenitor & Precursor CellsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201610
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.
Slide11Hemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201611
Slide12Medical ApplicationHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201612
Hemopoietic growth factors
are important products of
biotechnology companies. They are used clinically to increase marrow cellularity and blood cell counts in patients with conditions such as severe anemia or during chemo- or radiotherapy, which lower white blood cell counts (leukopenia). Such
cytokines may also increase the efficiency of marrow transplants by enhancing cell proliferation, enhance host defenses in patients with infectious and
immunodeficient
diseases, and
improve treatment
of some parasitic diseases
.
Slide13Bone MarrowHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016
13
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: Blood-forming
red bone marrow, whose color is produced by an abundance of blood and hemopoietic cells.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
.
Slide14Bone MarrowHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201614
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
.
Slide15Bone MarrowHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201615
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.
Slide16Figure 13-4
Slide17Figure 13-5
Slide18Medical ApplicationHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016
18
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 areproduced 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
.
Slide19Maturation of ErythrocytesHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201619
Several major changes take place during
erythropoiesis:
Cell and nuclear volumes decrease.The nucleoli diminish in size and disappear. Chromatin density increases until the nucleus presents a pyknotic appearance and is finally extruded from the cell.There is a gradual decrease in the number of
polyribosomes (basophilia), with a simultaneous increase in the amount of hemoglobin (a highly eosinophilic protein). Mitochondria and other organelles gradually disappear.
Slide20Maturation of ErythrocytesHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201620
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
.
Slide21Figure 13-6
Slide22Figure 13-7
Slide23Maturation of GranulocytesHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201623
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:Made initially are the azurophilic granules, which contain lysosomal hydrolases, stain with basic dyes, and are
basically similar in all three types of granulocytes. Golgi activity then changes to produce proteins for the specific granules, whose contents differ
in each of the three types of
granulocytes.
Slide24Figure 13-8
The most immature cell
Slide25Medical ApplicationHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201625Before 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 theleft
,” is clinically significant, usually indicating a bacterialinfection.
Slide26Maturation of GranulocytesHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201626
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:
The granulopoietic compartment in active marrow.Storage
as mature cells in
marrow
until release.
The
circulating
population
.
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.
Inflamed connective tissue
.
Slide27Figure 13-12
Slide28Maturation of GranulocytesHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201628
Neutrophilia
, an
increase in the number of circulating neutrophils, does not necessarily imply an increase in granulopoiesis. 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.
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.
Slide29Maturation of AgranulocytesHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201629
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.
Slide30Maturation of AgranulocytesHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201630
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.
Slide31Medical ApplicationHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201631
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
.
Slide32Origin of PlateletsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201632
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
.
Slide33Figure 13-13
Slide34Origin of PlateletsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201634
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
μ
m), wide (2-4
μ
m) branching processes called
proplatelets
.
These
cellular extensions
penetrate the sinusoidal endothelium
and are exposed in the circulating blood
of the sinusoids
Slide35Figure 13-13
Slide36Figure 13-13
Slide37Figure 13-5
Slide38Origin of PlateletsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201638Internally
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.
Slide39Origin of PlateletsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201639Mature 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.
Slide40Figure 13-14
Slide41Thank You
Slide42Hemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201642