About Hematopoiesis.Hematopoietic stem cell and its proginators.Cytokines and its role in Hematopoiesis

1. hematopoiesis

2. Contents
 Introduction
 Hematopoietic stem cell and its
proginators
 Role of cytokines in
hematopoiesis
 Conclusion
 Reference

3. Hematopoiesis
 Is the formation of blood cellular components.
All cellular blood components are derived
from haematopoietic stem cells.

4. STEM CELLS
 They can proliferate extremely well
 They are self-renewing
 They can differentiate into several (at
least 2) different cell-types
 They can reconstitute tissues after
injury
 DIFFERENT TYPES OF STEM CELLS:
 TOTIPOTENT STEM CELLS: Have the ability to
generate an entire organism. Only embryonic stem
cells are able to do this
 MULTIPOTENT STEM CELLS: Have the ability to
differentiate into several different cell types, for ex,
HSCs

6. Locations
 In developing embryos, blood formation occurs
in aggregates of blood cells in the yolk sac,
called blood islands.
 As development progresses, blood
formation occurs in the spleen, liver and lymph
nodes.
 When bone marrow develops, it eventually
assumes the task of forming most of the blood
cells for the entire organism.

7. Extra medullary
 In some cases, the liver, thymus, and spleen
may resume their haematopoietic function, if
necessary. This is called extramedullary
haematopoiesis.

8. Maturation
 As a stem cell matures it undergoes changes
in gene expression that limit the cell types that
it can become and moves it closer to a specific
cell type.
 These changes can often be tracked by
monitoring the presence of proteins on the
surface of the cell. Each successive change
moves the cell closer to the final cell type.

9. Determination
 Cell determination appears to be dictated by
the location of differentiation.
 , the thymus provides an ideal environment for
thymocytes to differentiate into a variety of
different functional T cells. For the stem cells
and other undifferentiated blood cells in the
bone marrow.
 the colony stimulating factors and other factors
of the haematopoietic microenvironment
determine the cells to follow a certain path of
cell differentiation

10. SOURCES OF HSCs
 Bone marrow &
mobilized peripheral
blood
 Umbilical cord
 Embryonic stem cells

11. HALLMARKS OF HSCs
 SELF-RENEWAL: Ability to make copies with
the same or very similar potential.
 DIFFERENTIATION: Differentiate into several
different cellular components of blood.
 MIGRATION: Occurs at specific times during
development(ie, seeding of fetal liver,spleen
and eventually,bone marrow) and certain
conditions(eg, cytokine-induced
mobilization)later in life

12. HAEMATOPOIESIS

13. Hematopoietic Stem Cells and Progenitors
 All of the mature blood cells in the body are
generated from a relatively small number of
hematopoietic stem cells (HSCs) and progenitors.
 HSCs are able to generate every lineage found in
the hematopoietic system including red blood
cells, platelets, and a variety of lymphoid and
myeloid cells.
 Each of these cell types can be generated from a
single HSC, and each HSC has an enormous
capacity to generate large numbers of these cells
over many years.

14.  HSCs are primarily found in the bone marrow.
 they are present in a variety of other tissues including
peripheral blood and umbilical cord blood, and are
found at low numbers in the liver, spleen, and perhaps
many organs.
 HSCs are small cells with minimal cytoplasm, and they
express high levels of the multidrug resistant (MDR)
proteins and high levels of aldehyde dehydrogenase
(ALDH).
 These cells tend not express surface markers seen on
mature HSCs but can express low levels of the thy-1
surface protein and relatively high levels of the sca-1
surface marker.
 HSCs generate the multiple hematopoietic lineages
through a successive series of intermediate

15.  These include common lymphoid
progenitors(CLPs),which can generate only
B,T, and NK cells, and common myeloid
progenitors (CMPs), which can generate only
red cells, platelets, granulocytes, and
monocytes.
 Downstream of the CLPs and CMPs are more
mature progenitors that are further restricted in
the number and type of lineages that they can
generate.
 terminally differentiated cells are produced that
cannot divide and undergo apoptosis after a

17. MYLOID LINEAGE:
Mononuclear Phagocytes
 The mononuclear phagocytic system consists of monocytes
circulating in the blood and macrophages in the tissues .
 During hematopoiesis in the bone marrow, granulocyte-
monocyte progenitor cells differentiate into promonocytes,
which leave the bone marrow and enter the blood, where
they further differentiate into mature monocytes.
 Monocytes circulate in the bloodstream for about 8 h, during
which they enlarge; they then migrate into the tissues and
differentiate into specific tissue macrophages or, into
dendritic cells.
 : The cell enlarges five- to tenfold; its intracellular organelles
increase in both number and complexity; and it acquires
increased phagocytic ability, produces higher levels of
hydrolytic enzymes, and begins to secrete a variety of soluble
factors.

18. Monocytes
They are normally refered to as the
mononuclear phagocytic cells
.Found as free circulating cells in
the blood stream. They constitute
approximately 4-10% of the
nucleated cells in the blood. The
monocyte has a diameter of 12-
17mM with a characteristic
Horseshoe-shaped nucleus and
cytoplasmic granules. The
monocytes are the precurssors of
the tissue-bound macrophages.
They migrate to the tissues and
becomes macrophages.

19. Macrophages
 After the monocytes become macrophages most importently
the phagocytic property of the cell increased.
 It contains azurophilic lysosomal granules that contains
myeloperoxidase, lysozyme, acid hydrolases such as beta
glucuronidase, phosphate etc.
 The activated macrophages express high level of MHC class II
molecules, the ones that are required to present the antigen to
the T helper cells, which is prerequisites for immune response.
Due to this activity the macrophages are refferd to as “antigen
presenting cells”
 Macrophages express certain characteristic molecules on their
cell surface, which can be identified by specific monoclonal
antibodies. A systematic nomeclature has been attributed to
those molecules, in which CD stands for cluster of differentiation.
They are assigned with different numbers according to the
monoclonal antibodies to which they respond. The different CD
markers of the macrophages are CD64, CD32 and CD64 which
acts as Fc receptor of the antibody

20.  Alveolar macrophages in the lung
 Histiocytes in connective tissues
 Kupffer cells in the liver
 Mesangial cells in the kidney
 Microglial cells in the brain
 Osteoclasts in bone

21. Granulocytic Cells
Neutrophils from the major part of the
white blood carpusles(40-75%) they are
motile short lived cells with multilobed
nucleus, the cytoplasm contains granules
which do not take up acidic or basic stains
strongly and hence named neutrophils.
The major function of the neutrophils is
phagocytosis which is similar to
macrophages. Neutrophils can attack and
destroy bacteria and viruses even in the
circulating blood, when a tissue is
damaged or inflamed, the neutrophils
reach that area along with macrophages
destroy the unwanted tissues by
phagocytosis

22. These are acidophilic leucocytes
and are called eosinophils because,
eosin, an acidic dye stains the granules of
the cytoplasm of these cells intensely. The
granules are rich in hydrolytic enzymes.
The nucleus is usually bilobed or ellipsoid.
They are about 2-5% of the leucocytes in
healthy individuals.
Increase in number of eosinophils
(eosinophilia) is observed in allergic
reaction especially during infection with
intestinal parasites. At the time of parasitic
infection, degranulation of eosinophils
occurs and hydrolytic components of the
granules are released, which kill the
parasites.
Eosinophils

23. These cells are named so,
because of their cytoplasm
containing granules that stains
with basic dye. Basophils
constituets about 0.4% of white
cells. The basophils granules
are belived to contain heparin,
histamine, serotonin, platelet
activating factor and other
vasoactive amines that may be
released at the site of
inflammation or regions of
immediate hypersensitivity
reaction.
Basophils

24. Platelets
Platelets, also
called thrombocytes (thromb- + -cyte,
"blood clot cell), are a component of
blood whose function (along with
the coagulation factors) is to stop
bleeding by clumping and clotting
blood vessel injuries. Platelets have no cell nucleus: they
are fragments of cytoplasm that are
derived from the megakaryocytes of
the bone marrow, and then enter the
circulation.These unactivated platelets are
biconvex discoid (lens-shaped)
structures, 2–3 µm in greatest
diameter.

25. Erythropoiesis
 This occurs entirely in the red bone
marrow. Red marrow can be found in
vertebrae, ribs, skull, sternum, scapula, and
proximal ends of the limb bones (known as
the trabecular area).
 Red marrow is also known as myeloid
tissue. It is not generally found in other areas
of the long limb bones; which are instead filled
with fatty yellow marrow During childhood, red
marrow is far more extensive.

26.  The haemocytoblast, in the presence of Multi-CSF,
will develop into a Progenitor cell. These cells will
go on to form all types of blood cell,
except Lymphocytes. In the presence of EPO, the
progenitor cell will become a proerythroblast.
 In the presence of EPO, this will develop into
a basophilic erythroblast
 In the presence of more EPO, this will develop into
a polychromatophilic erythroblast, then
a normoblast, which will then eject its nucleus, and
become a reticulocyte, before finally becoming a
fully formed RBC.

27. LYMPHOID LINAGE:
 Lymphocytes constitute 20%–40% of the body’s white blood
cells and 99% of the cells in the lymph.
 These lymphocytes continually circulate in the blood and
lymph and are capable of migrating into the tissue spaces
and lymphoid organs,
 Two morphological distinct lymphocytes can be observed in
the blood the first type is the small agranular lyphocyte
having high nuclear-to-cytoplasm ratio.these lymphocytes are
further divided into two types they are T and B lymphocytes
 The second type is a large cell, which is granulated, and
posses low nuclear-to-cytoplasmic ratio. They are called as
large granulated lymphocytes. Lymphocytes normally
possess specific receptors for antigens and thus mediate
specific immunity.

28. T lymphocytes
 The T lymphocytes are found in the bone marrow as pre T
lymphocytes. Then they enter the thymus to become matured
T lymphocytes. Most of the circulating lymphocytes are T
lymphocytes and contribute to about 80% of the lymphocyte
population.
 The T cells play two important function-effector and
regulatory.
 The effector function includes cytolysis of cell infected with
microbes and tumour cells and lymphokine production. The
regulatory functions are either to increse or to supress other
lymphocytes and accessory cells.
 T cells are two types:
 T helper cells
 T cytotoxic cells

29.  T helper lymphocytes that help B lymphocytes to
produce antibiodies and help phagocytes to
destroy ingested microbes.
 T cytotoxic lymphocytes that kill cells harbouring
intracellular microbes.
 These two types of T cells shows differences in
their surface markers. The T helper cells express
CD4 marker on their cell surface, whereas the T
cytotoxic cells express CD8 marker on their cell
surface. Thus T h cells will be referred to as CD4
cells and Tc cells as CD8 cell.

30. B lymphocytes
 Bone marrow is its major site of maturation
 A single B cell has an identical binding site for antigen.
Among the other molecules expressed on the membrane of
mature B cells are the following: B220 (a form of CD45) is
frequently used as a marker for B cells and their precursors.
 They are very important in antibody-mediated immunity as
they secrete specific immunoglobulins in response to
antigenic stimulus.
 The B cells are of two subunits.
 T-cell-independent cell: which do not require the help of T h
cells for the production of immunoglobulins.
 T-cell-dependent cell: which require the help of T h cells for
the production of immunoglobulins.

31.  The dendritic cell (DC) acquired its name because it is covered with
long membrane extensions that resemble the dendrites of nerve
cells.
 the same major function, the presentation of antigen to TH cells
 The dendritic cell decend from the myeloid cell lineage. They
circulate in blood as immature cells and mature as complete
dendritic cell in the tissue.
 The dendritic cell express high level of both class I and class II
MHC molecules. They are potent antigen-presenting cells. Most
dendritic cells process the antigen and present it to T h cells.
 There are different types of dendritic cells
 Langerhans’ cells
 Interdigitating dendritic cells
 Interstitial dendritic cells
 Veiled cells
DENDRITIC CELLS

32. Natural killer cells
 NK cells were subsequently shown to play an
important role in host defense both against tumor
cells and against cells infected with some, though
not all, viruses.
 These cells, which constitute 5%–10% of
lymphocytes in human peripheral blood,
 they can recognize potential target cells in two
different ways.
 NK cells express CD16, a membrane receptor for
the carboxyl-terminal end of the IgG molecule,
called the Fc region, they can attach to these
antibodies and subsequently destroy the targeted
cells

33. HAEMATOPOIETIC GROWTH FACTORS
 The discovery of growth factors has been a major advance in
this area. It is now known that a number of cytokines play a
role in the differentiation of blood cells. Many cytokines that
influence the development of the various hematologic cells
have been identified.
 It is the balance of these cytokines within the
microenvironment surrounding the pluripotent stem cell and its
subsequent lineage that determines the pathway of
differentiation.
 Growth factors play a role in hematopoiesis not only by
causing differentiation of stem cells toward a particular cell
type, but also by inducing the proliferation of cells.

35. Role of cytokines in
hematopiosis
 Early work in Australia and Israel demonstrated that soluble factors
could support the growth and differentiation of red and white blood
cells.
 The first of these soluble factors to be characterized, erythropoietin,
was isolated from the urine of anemic patients and shown to support
the development of red blood cells.
 Many cytokines have been shown to play essential roles in
hematopoiesis
 During hematopoiesis, cytokines act as developmental signals that
direct commitment of progenitor cells into and through particular
lineages
 A myeloid progenitor in the presence erythropoietin would proceed
down a pathway that leads to the production of erythrocytes.
 Suitable concentrations of a group of cytokines including IL-3, GM-
CSF, IL-1, and IL-6 will cause it to enter differentiation pathways that
lead to the generation of monocytes, neutrophils, and other leukocytes

36. Summary
 In our body each and every process will takes
place through blood only, blood cells plays an
important role in the body i.e immune function,
oxygen supply etc…. Hence the synthesis of
blood cells is essential way to control our immune
system. All blood cells arise from a single type of
a cell i.e HSC which is totipotent in nature having
self-renewing capacity. Hsc gives rise to two
lineage 1.lymphoid and myloid lineage. then these
leads to the synthesis of different immune cells
like monocytes, macrophages, neutrophils,
eosinophils, basophils, platlets involved in
immune function and these immune cell
production depends on the secretion of cytokines
from the cell when all are independent in nature.

37. Reference
 Kuby,’Immunology’-sixth edition
 www.news-medical.net
 http://en.m.wikipedia.org
 I Kannan, immunology.

38. Vikas CJ
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