Dr. Emad I H Shaqoura - PowerPoint Presentation

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Dr. Emad I H ShaqouraM.D, M.Sc. AnatomyFaculty of Medicine, Islamic University-GazaFeb., 2016

Hemopoiesis

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HemopoiesisHemopoiesis (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

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Figure 13-1

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Stem Cells, Growth Factors,& DifferentiationHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016

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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 CellsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016

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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.

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Figure 13-2

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Progenitor & Precursor CellsHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016

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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

).

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Progenitor & 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.

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Figure 13-3

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Progenitor & 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.

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Hemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201611

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Medical 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

.

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Bone MarrowHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016

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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

.

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Bone 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

.

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Bone 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.

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Figure 13-4

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Figure 13-5

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Medical ApplicationHemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 2016

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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

.

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Maturation 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.

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Maturation 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

.

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Figure 13-6

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Figure 13-7

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Maturation 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.

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Figure 13-8

The most immature cell

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Medical 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.

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Maturation 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

.

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Figure 13-12

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Maturation 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.

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Maturation 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.

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Maturation 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.

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Medical 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

.

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Origin 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

.

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Figure 13-13

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Origin 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

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Figure 13-13

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Figure 13-13

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Figure 13-5

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Origin 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.

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Origin 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.

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Figure 13-14

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Thank You

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Hemopoiesis, Dr. Emad I Shaqoura, IUG Faculty of Medicine, 201642