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LEARNING OBJECTIVES
EMBRYOLOGICAL DEVELOPMENT OF BLOOD ELEMENTS
‘ HEMATOGENESIS Learning Objectives:
At the end of lecture the student should be able to understand :
1. Define haemangioblasts, and the processes of vasculogenesis and
angiogenesis
2. Factors and hormones involved in prolifaration and maturation of blood
cells
3. Differentiate between Primitive Versus Definitive Hematopoiesis
4. Organs involved in the process of hematopoiesis at various stages of development
5. Describe the following:
a. Yolk Sac Hematopoiesis
b. Fetal Liver Hematopoiesis
c. The Bone Marrow Hematopoiesis
6. B and T cell development processes
7. Development and maturation process of various cellular components of blood
LECTURE OUTLINE
EMBRYOLOGICAL DEVELOPMENT OF BLOOD ELEMENTS
‘ HEMATOGENESIS ’
BLOOD:

Blood is a specialized connective tissue because it comprises of
cells and intercellular matrix which is fluid rather than gel in
nature.

It is an opaque turbid fluid which looks bright scarlet in systemic
arteries and dark red in systemic veins.
OR

It is a heterogeneous fluid consisting of a clear liquid (plasma) and
formed elements (cells / corpuscles).

It is a vehicle which maintains a vast chemical traffic through
body moving hormones, oxygen, nutrients, antibodies,
catecholamines, cells as well as infestents and toxic compounds.
 Quantity in normal adults 4.5 to 5.5 litres.
BLOOD CORPUSCLES / CELLS:
1. Erythrocytes / Red Blood Cells (R.B.C)
2. Leukocytes / White Blood Cells (W.B.C)
3. Thrombocytes / Platelets
Each with structure, quantity, function and abnormalities.
Remarks to physiology of blood
1. Main functions of blood

Transport of various substances (O2,CO2, nutrients, metabolites,
minerals, ......)

Transport of heat (heating, cooling)

Signal transmission (hormons,...)

Carrier proteins – e.g. albumin

Buffering and defence systems (antibodies, white blood cells,
oxidants-antioxidants, buffer systems)

Remove products of metabolism

Body homeostasis-temperature, water, electrolytes
2. Composition of blood

Blood cells (RBC, WBC, platelets)

Plasma(electrolytes,nutrients,metabolites,proteins,fat,
carbohydrates, vitamins, gases....)
Development of blood cells
 Hematopoietic tissues
 red bone morrow (in adult)
 spleen, liver, other organs (pathologic conditions).

Pluripotent stem cells
 myeloid, erytroid, lymphoid
 precursor cells
 hematopoietic growth factors

Myeloid precursor cells  myelopoiesis  monocytes  tissue
macrophages

 (in bone morrow)

 mast cells,
maturation
eosinophils,
neutrophils,
basophils.
Lymphoid precursor cells
 lymphopoiesis  LymphocyteT, Lymphocyte B
 (in spleen and lymph nodes)
Maturation.
Factors and hormones involved in prolifaration and
maturation of blood cells

Erytropoietin (EPO) proliferation and maturation of ER
(from kidney)

Thrombopoietin  prolifaration and maturation of
(from kydney)
megacaryocytes  platelets
 Paracrine factors:
- colony stimulating factors (CSF)
(in bone morrow)
- stem cells factor  release CSF and IL
3, 6, 11, 12
 Androgens, Thyroid hormons
CSF and IL formation are inhibited by TGF beta and by TNF alfa
•
Early human (before 16 days gestation) do not have blood.
•
Instead the embryo obtains all the required nutrients and oxygen
from simple diffusion.
Waste products also diffuse out of the
embryo into the mother’s circulation.

Once the embryo reaches a certain size, simple diffusion is not
sufficient
to
bring
nutrients
or
remove
waste
products
necessitating the development of a circulatory system.
Various Blood Cell Types Found in the Adult:
Cells/liter in human blood
1 X 109
2 X 109
1 X 108
4 X 108
5 X 109
2 X 108
4 X 107
3 X 1011
Development of Blood Vessels :
5 X 1012
Blood vessels are formed in two ways:
i.
Vasculogenesis in which vessels arise from determined groups of
mesodermal cells (islets of haemangioblasts).
ii.
Angiogenesis in which vessels arise (sprout) from preexisting
vessels.
Blood vessels first arise from extrra embryonic mesoderm of yolk sac,
body stalk and chorion ; while 2 days
later on they develop in
intraembryonic mesoderm.

Haemangioblasts are determined mesodermal cells which
differentiate into angioblasts (blood vessel forming cells) and
haematopoietic cells (blood forming cells).
Primitive Versus Definitive Hematopoiesis:
Primitive Erythropoiesis:

Red Blood cells have nuclei

Few white blood cells produced.
Definitive Erythropoiesis:

Red Blood cells do not have nuclei.

Many types of white blood cells produced.
Lateral Plate Mesoderm:

The lateral plate mesoderm is a source of the progenitors for the
first blood cells in the embryo.

Gives rise to blood and to parts of the body wall and outside of the
gut.
The Hemangioblast:
Certain studies have demonstrated that there are cells in the early
embryo that have the potential to develop into both blood cells and
vascular endothelial cells. These cells are termed hemangioblasts and
are derived from the lateral plate mesoderm. Hemangioblasts are
likely to be involved in both primitive and definitive hematopoiesis as
well as blood vessel formation (vasculogenesis).
Where do Blood Cells Arise From in the Embryo?
1. Cells in Lateral Plate Mesoderm migrate to regions that will form
the blood.
2. Hemangioblasts in the “blood islands” of the embryonic yolk sac
give rise to primitive hematopoiesis.
3. Hemangioblasts derived from the Aorta-Gonad-Mesonephros (AGM)
region surrounding the dorsal aorta are contribute to definitive
fetal
liver
and
bone
marrow
hematopoiesis.
Clusters
of
hematopoietic cells are found attached to the ventral side of the
aorta.
Stem Cells:
All the blood cell lineages are derived from a single multi-potential
hematopoietic stem cell. The stem cell can self-renew and can also give
rise to more committed progeny whose developmental fate is more
restricted along one or more differentiation pathways.
Blood Cell Development:
In mammals, blood cell development takes place in
Three Main Organs :

Yolk Sac,

Fetal Liver And

Bone Marrow And
Two Discrete Stages

Primitive And

Definitive.
1. Yolk sac hematopoiesis

Occurs in the embryonic yolk sac from about day 7.5-11 of mouse
development and week 3-6 of human development.

Primitive nucleated erythrocytes.

Some granulocytes and macrophages.

Lymphoid lineages absent.
2. Fetal liver hematopoiesis

Occurs in the mouse fetal liver from about 9 days of gestation till
soon after birth and in the human fetal liver between 6 and 22
weeks of gestation.

Definitive enucleated erythrocytes.
Both myeloid and lymphoid lineages are present.

3. Bone marrow hematopoiesis

Occurs in the bone marrow from late in gestation (day 17-18
untilbirth in mice, week 22-birth in humans) throughout the animal’s
life.


Definitive blood cells of all lineages.
T cells develop in the thymus.
Two possible models of changes in hematopoietic site for
blood formation:
Model #1: Yolk sac progenitors do not contribute to adult hematopoiesis.
Model #2: Yolk sac progenitors do contribute to adult hematopoiesis.
Yolk Sac Hematopoiesis (blood islands):
In the yolk sac, the first place of hematopoiesis mesenchymal cells
differentiate to clusters of hemangioblast cells.
The hemangioblasts
further differentiate into endothelial cells and primitive blood cells. This
is the first “blood vessel” like structure in the embryo.
Fetal Liver Hematopoiesis:

Colonized by definitive hematopoietic stem cells derived from the
AGM and possibly also from the yolk sac blood islands.

All blood cell types (except T cells) can differentiate in the fetal
liver.
The Bone Marrow Hematopoiesis:

Colonized late in embryogenesis by definitive hematopoietic stem
cells derived from the fetal liver.

All blood cell types (except T cells) can differentiate in the bone
marrow.
B Cell Development (Definitive Hematopoiesis:

Hematopoietic stem cells give rise to a lymphoid progenitor cell,
which is thought to be able to differentiate into both B cells and T
cells as well as NK cells.

This lymphoid progenitor can migrate to the thymus and initiate T
cell development or remain in the bone marrow to initiate B cell
development.

Bone marrow B cell development can be subdivided into various
stages: pro-B, pre-B, immature B and mature B cells.
B Cell Development is Dependent on Several Factors:
A.) The presence of bone marrow stromal cells providing cell-mediated
contacts.
B.) The presence of the cytokine IL-7 secreted mainly by the bone marrow
stromal cells.
C.) The productive rearrangement of the immunoglobulin genes.In the
common lymphoid progenitor both the immunoglobulin heavy and light
chains are in their germ-line configuration and must be rearranged to
generate an in-frame protein for B cell development to progress.
EFFECTOR CELLS :
Th- Helper Cell:
•
B Cell
•
Macrophage
•
Neutrophil (alternative path)
•
Mast Cell
•
Platelets.
Tc Cytotoxic Cell:
•
Dendritic Cell
•
Neutrophil
•
Eosinophil
•
Basophil
•
Erythrocyte
T - helper cell pathway:
Pluripotent Stem Cell:
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Lymphoid Stem Cell:
Daughter cell of the Pluripotent Stem Cell, this cell will divide to produce
progenitors to either B cell or T cell lines.
T cell progenitor leaves the bone marrow and settles in the thymus; will
produce Thymocyte cells in the thymus which can, in turn differentiate
into T helper cells, T killer cells, or T memory cells.
The Thymocyte:
The Thymocyte is located in the thymus and divides to produce mature T
effector cells…..
Th (helper)Tc (cytotoxic-killer) or Tm (memory).
Th (helper) cell:
When activated by an Antigen Presenting Cell like a macrophage with
antigen, the Th cell will induce rapid growth of white blood cells which
help fight infection.
Tc (cytotoxic/”killer”) cell pathway:
Pluripotent Stem Cell:
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Lymphoid Stem Cell:
Daughter cell of the Pluripotent Stem Cell, this cell will divide to produce
progenitors to either B cell or T cell lines.
The Thymocyte:
The Thymocyte is located in the thymus and divides to produce mature T
effector cells…..
Th (helper)Tc (cytotoxic-killer) or Tm (memory).
Tc (cytotoxic or “killer”) Cells…
Sometimes called CTLs (cytotoxic T lymphocytes, these may recognize
infected “self” cells and destroy them.
B cell pathway
Pluripotent Stem Cell:
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Lymphoid Stem Cell:
Daughter cell of the Pluripotent Stem Cell, this cell will divide to produce
progenitors to either B cell or T cell lines.
B Cell progenitor:
B Cell progenitor found in the bone marrow of higher vertebrates and the
Bursa of Fabricius in birds, these cells will produce antibody producing
B cells.
B Cell:
These are found in the blood and , when activated will produce
antibodies against particular antigens. Each cell produces antigen
specific antibodies of only one type.
Dendritic cell pathway:
Pluripotent Stem Cell:
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Myeloid Stem Cells:
Daughters of the Pluripotent Stem Cells, these are the progenitors of a
host of specialized white blood cells (WBCs), red blood cells (RBCs) and
the blood platelets which are crucial to blood clotting.
Granulocyte -Monocyte Progenitor cells can differentiate into
monocytes or neutrophils.
Monocytes… act as antigen presenting cells (APCs), as AntibodyDependent Cytotoxic Cells (ADCC) , and promote inflammation.
Dendritic Cell… like the macrophage, this cell is phagocytic it inhabits
the tissues looking for foreign intruders to devour.
Macrophage pathway:
Pluripotent Stem Cell:
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Myeloid Stem Cells… daughters of the Pluripotent Stem Cells, these
are the progenitors of a host of specialized white blood cells (WBCs), red
blood cells (RBCs) and the blood platelets which are crucial to blood
clotting.
Granulocyte -Monocyte Progenitor cells can differentiate into
monocytes or neutrophils.
Monocytes… act as antigen presenting cells (APCs), as AntibodyDependent Cytotoxic Cells (ADCC) , and promote inflammation.
Macrophage…functions as antigen presenting cell (APC), in
inflammation, and in ADCC (antibody-dependent cell-mediated
cytotoxicity.
Neutrophil Pathway:
Pluripotent Stem Cell:
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Myeloid Stem Cells… daughters of the Pluripotent Stem Cells, these
are the progenitors of a host of specialized white blood cells (WBCs), red
blood cells (RBCs) and the blood platelets which are crucial to blood
clotting.
Granulocyte -Monocyte Progenitor cells can differentiate into
monocytes or neutrophils.
Monocytes… act as antigen presenting cells (APCs), as AntibodyDependent Cytotoxic Cells (ADCC) , and promote inflammation.
Myeloid Stem Cells… daughters of the Pluripotent Stem Cells, these
are the progenitors of a host of specialized white blood cells (WBCs), red
blood cells (RBCs) and the blood platelets which are crucial to blood
clotting.
Granulocyte -Monocyte Progenitor cells can differentiate into
monocytes or neutrophils.
Neutrophils…function in antimicrobial activity, inflammation response,
and antibody-dependent, cell-mediated cytotoxicity (ADCC).
Basophil pathway
Pluripotent Stem Cell:
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Myeloid Stem Cells… daughters of the Pluripotent Stem Cells, these
are the progenitors of a host of specialized white blood cells (WBCs), red
blood cells (RBCs) and the blood platelets which are crucial to blood
clotting.
Basophil Progenitor… a product of the specialization of Myeloid stem
cells, this cell will produce either Mast Cells or Basophils.
Basophil…this IgE responsive cell is characterized by cytoplasmic
granules which, when released, function in destruction of parasites and
also in allergic reactions. The cell releases histamine and platelet
activator and other chemical signals.
Platelet pathway
Pluripotent Stem Cell:
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Myeloid Stem Cells… daughters of the Pluripotent Stem Cells, these
are the progenitors of a host of specialized white blood cells (WBCs), red
blood cells (RBCs) and the blood platelets which are crucial to blood
clotting.
Megakaryocyte…fragments into subcellular pieces called platelets.
Platelets…are blood elements without nuclei that circulate and are
involved in blood clotting and inflammation.
Erythrocyte Pathway
Pluripotent Stem Cell
This is the undifferentiated precursor to all of the blood cells, red and
white, and other immune effector cells, and platelets.
Myeloid Stem Cells… daughters of the Pluripotent Stem Cells, these
are the progenitors of a host of specialized white blood cells (WBCs), red
blood cells (RBCs) and the blood platelets which are crucial to blood
clotting.
Erythroid Progenitor…derived from a myeloid stem cell, this is
destined to produce the most common blood cell, the erythrocyte.
Erythrocytes…or red blood cells (RBCs)are enucleated cells that travel
throughout the Circulatory System and carry Oxygen to all parts of the
body via the abundant hemoglobin found within them.
REFRENCES
Thanks are due to many books and internet sources. Especially
followings:
•
“Hematopoiesis from pluripotent stem cells to mature,
differentiated,cellular effectors of immunity and more BY Richard
A. Poirier for HHMI/Harvard Immunology Summer Project 2004
•
Lineages and Stem Cells:B-cell Development
•
Pathophysiology of red and white blood cells, disturbances of
hemostasis and coagulation BY Prof. J. Hanacek, MD, PhD.