Manipal International University, Malaysia

ASSIGNMENT 3

NAME: VENGGADANAATHAN A/L K. SALVAM

STUDENT ID: 1002223006
PROGRAMME: FOUNDATION IN SCIENCE (FIS)
SCHOOL: SCHOOL OF ENGINEERING AND COMPUTING (SOEC)
COURSE CODE / TITLE: FSC 3224 Biology 2
INTAKE: OCTOBER 2022
SEMESTER: 3
TYPE OF ASSESSMENT: Assignment
LECTURER: MS SARATHATHEVI THRICHELVAM
 TITLE: How is hematopoietic stem cell involved in production of red blood cell?

INTRODUCTION

WHAT IS HEMATOPOIETIC STEM CELL?

Hematopoietic stem cells (HSCs) are a type of pluripotent stem cells found mainly in the
bone marrow of adults and in small amounts in peripheral blood and cord blood. These
specialized cells are responsible for making different blood cells continuously throughout a
person's life. "Haematopoiesis" refers to the ability to produce different types of blood cells,
while "stem cells" refer to the ability to self-renewal and differentiate into specific cell types.

SUBCATEGORY

A colony forming unit is a subtype of CSH. (The meaning of this term is different from
microbial colony-forming units, which are cell-counting units.) There are different types of
HSC colony-forming units:

• Colony-forming unit-granulocytes-erythrocytes-monocytes-superhuman (CFU-

GEMM)
• Colony-forming unit lymphocytes (CFU-L)
• erythrocyte colony-forming unit (CFU-E)
• Colony-forming unit–granulocyte–macrophage (CFU-GM)
• Colony-forming unit–megakaryocyte (CFU-Meg)
• Colony-forming unit–basophil (CFU-B)
• Colony-forming units–eosinophils (CFU-Eos)

The CFUs above are based on lineage. Another CFU, the splenic colony-forming unit (CFU-
S), underlies the in vivo cloning process, in which injected bone marrow cells grow in the
spleens of mice. irradiated 8-8 days later. It depends on the clonal ability of the mature
hematopoietic cell within the cell. 12nd. Although widely used in early studies, it is now
thought to measure more mature progenitor cells or transport-promoting cells rather than
stem cells.

WHERE DOES HEMATOPOIESIS OCCUR?

The most common site of blood cell production is the spongy tissue inside bones called bone
marrow. Haematopoiesis that occurs in the bone marrow is called medullary haematopoiesis.
Blood cells are made in the bone marrow and released into the bloodstream.
Less commonly, haematopoiesis can also occur in other parts of the body, such as the liver
and spleen. Haematopoiesis that occurs outside the bone marrow is called extramedullary
haematopoiesis. Haematopoiesis occurs at different sites before and after birth.

• BEFORE BIRTH

Blood cell production begins in the uterus. It begins with the yolk sac, the structure that
surrounds the embryo in early pregnancy. Near the end of pregnancy, most blood cells are
produced in the bone marrow. Important milestones of hematopoiesis during pregnancy are:

Week 3:

Some red blood cells are produced in the yolk sac and are slightly less developed than those
produced in adulthood.

2nd and 3rd month:

Red blood cells and platelets are made in the liver and spleen. White blood cells are made in
the liver, spleen, and thymus.

5th month:

Most blood cell production takes place in the bone marrow. The thymus, spleen, and other
lymphoid tissues also produce some types of white blood cells.

• AFTER BIRTH

From infancy to adulthood, most blood cell production takes place in the bone marrow. A
specific type of white blood cell called a lymphocyte also occurs in the thymus. Illness
creates exceptions. If there is a disease that prevents the bone marrow from producing enough
blood cells, haematopoiesis may shift to the site of blood cell production before birth. Blood
cell production may shift to the liver, spleen, or lymph nodes.

HSCs have two basic properties:

• Self-renewal:

Hematopoietic stem cells can divide and make identical copies through a process called
self-renewal. This ability ensures a constant pool of stem cells to sustain blood cell
production throughout life.

• Difference:
HSCs have the unique ability to differentiate into various specialized blood cells, including:

 Red blood cells (erythrocytes):

Responsible for transporting oxygen throughout the body.

 White blood cells (white blood cells):

Part of the immune system that protects the body against infection.

 Platelets (thrombosis):

Necessary for blood clotting to prevent excessive bleeding.

This process by which HSCs differentiate into specialized blood cells is called haematopoiesis.
HSCs are regulated by various growth factors and cytokines in the bone marrow
microenvironment, which determine their fate and the type of blood cells they will produce.
Hematopoietic stem cells play a vital role in replenishing the blood cell population, ensuring
the body's ability to maintain a balanced circulatory system and efficient functioning. They are
also the basis for bone marrow transplants, a medical procedure used to treat certain blood
disorders, cancers, and other conditions by replacing damaged or disordered blood cells.
function using healthy cells from a compatible donor.
WAYS OF PRODUCTION OF RED BLOOD CELLS FROM HEMATOPOIETIC STEM CELLS

Hematopoietic stem cells (HSCs) are pluripotent cells found in bone marrow and other
tissues that have the remarkable ability to differentiate into different types of blood cells,
including red blood cells (RBCs), white blood cells (WBC) and platelets. The process by
which HSCs produce mature blood cells is called haematopoiesis.

Specifically, in the context of red blood cell production, this process is known as
erythropoiesis. Here is how hematopoietic stem cells are involved in the production of red
blood cells: Stimulating erythropoiesis (EPO):

1. Formation of Proerythroblast:

Red blood cell production begins with the differentiation of hematopoietic stem cells
(HSCs) into common myeloid progenitor cells (CMPs) under the influence of various
growth factors and cytokines. CMP then differentiates into pro-erythroblasts, which are
the first precursors of red blood cells.

2. Differentiation stages:

Protoblasts undergo a series of maturation steps, each of which is characterized by

specific changes in cell morphology and gene expression. These stages include basophils,
polychromatic, and orthochromatic erythroblasts.

3. Nucleus Extrusion:

As erythroid erythrocytes mature, they release their nucleus and most of their
organelles. This process is called nucleation and is necessary to make room for more
haemoglobin, thereby increasing the oxygen-carrying capacity of the developing red
blood cell. The cells that form is called reticulocytes, which are an immature form of red
blood cells.

4. Reticulocyte maturation:

The reticulocytes are then released into the bloodstream and travel to the bone marrow
or spleen, where they continue to mature into fully functional red blood cells (mature
red blood cells). During this maturation, reticulocytes shed their remaining organelles
and the reticulum inside the cell disappears, resulting in a mature biconcave disc-shaped
red blood cell.

5. Circulation

Mature red blood cells travel through the blood, carrying oxygen from the lungs to
various tissues and organs in the body.

6. Commitment to erythroid lineage

Under the influence of specific growth factors such as erythropoietin (EPO), which is
produced by the kidney in response to low oxygen levels, disseminated myeloid
progenitor cells continue to differentiate into red blood cell progenitor cells. , also
known as erythroblasts.

It is important to note that this process is tightly regulated to maintain the correct
balance of different types of blood cells in the body. Various factors and signals, such
as growth factors, cytokines, and hormones, play an important role in controlling
haematopoiesis and ensuring the continued production of functional blood cells. ,
including red blood cells.
 1. FORMATION OF ERYTHROBLASTS

Red blood cell progenitor cells, also known as erythrocytes, go through a series of
developmental stages as they progress into mature red blood cells. These stages include pro-
erythrocytosis, basophilic erythrocytosis, polychromic erythrocytosis, and orthocytopenic
erythropoiesis. At each stage, cells undergo specific morphological and physiological
changes. They begin to synthesize haemoglobin, the iron-containing protein that binds
oxygen and gives red blood cells their characteristic red color.

When HSCs commit to the erythrocyte lineage and become pro-erythroblasts, they begin to
undergo active cell division and maturation. Protoblasts are characterized by large size,
prominent nucleus, and abundant cytoplasm. Under the influence of erythropoietin and other
growth factors, erythroblasts mature into basophils. At this point, they accumulate
haemoglobin, the protein that binds oxygen. Basophilic erythroblasts then progress through
several additional stages, including polychromatic and orthochromatic erythroblasts. Each
stage is marked by specific changes in the appearance of the cytoplasm and nucleus, as well
as an increase in the haemoglobin content.

2. DIFFERENTIATION STAGES

Hematopoietic stem cells (HSCs) differentiate into common myeloid progenitor cells (CMPs)
before producing several types of blood cells, including red blood cells. Here is a modified
explanation:

Differentiation into common myeloid progenitor cells (CMPs):

Hematopoietic stem cells (HSCs) are pluripotent cells that reside in the bone marrow and can
differentiate into different types of blood cells. When HSCs receive specific signals from the
bone marrow microenvironment and are exposed to various growth factors and cytokines,
they undergo differentiation into different types of progenitor cells. One of these types of
progenitor cells is the common myeloid progenitor cell (CMP). The process of differentiation
from HSCs to CMPs involves the activation of specific genetic programs that lead to changes
in gene expression and determine cell fate. As CMPs are formed, they lose some of the
pluripotency properties of HSCs and become more involved in the production of myeloid
cells, including red blood cells.
Ability to differentiate into many types of blood cells:

CMPs are pluripotent progenitor cells that can differentiate into several types of myeloid
cells, including red blood cells (erythrocytes), granulocytes, monocytes, and platelets. The
differentiation process is tightly regulated by a network of transcription factors and signalling
pathways, influenced by the microenvironment and various growth factors. The fate of the
CMP is determined by the specific combination of transcription factors and the signals it
receives during differentiation. In the context of erythropoiesis, the presence of erythropoietin
(EPO) is a key factor in the differentiation of CMPs into erythrocytes, which eventually
mature into erythrocytes.

Differentiate into erythrocytes:

Under the influence of erythropoietin (EPO), CMP receives the necessary signals to commit
to erythropoiesis and differentiate into erythrocytes, the precursors of erythrocytes. EPO is a
hormone produced mainly by the kidneys in response to low blood oxygen levels. EPO binds
to CMP receptors and stimulates the expression of specific genes that promote the
differentiation of CMPs into erythroblasts. The erythrocytosis phase is characterized by the
accumulation of haemoglobin, the oxygen-carrying protein necessary for the functioning of
red blood cells. As red blood cells mature through different stages, they lose their nucleus,
become reticulocytes, and eventually develop into fully mature red blood cells that are
released into the bloodstream to perform an important role in oxygen transport. and gas
exchange.

In summary, hematopoietic stem cells differentiate into common myeloid progenitor cells
(CMPs), which can produce several types of blood cells, including red blood cells.
Differentiation is regulated by various growth factors and cytokines, with erythropoietin
playing an important role in promoting CMP commitment to erythroid lineage and their
subsequent differentiation into mature erythrocytes. erythrocytes and erythrocytes.
General processes of hematopoietic stem cell differentiation. Long-lived hematopoietic stem
cells (LT-HSCs) differentiate into common lymphoid progenitor cells (CLPs) and common
myeloid progenitor cells (CMPs). CLP is involved in lymphangiogenesis and differentiation
into B cells (BC), T cells (TC) and natural killer T cells (NKT) (1). CMP is involved in
erythropoiesis and can differentiate into erythrocytes and platelets (2). CMPs can also
differentiate into granulocyte-macrophage (GMP) precursors and then differentiate into
granulocytes (neutrophils (NØ), eosinophils, basophils, and mast cells ) and MC "like a
FEMALE". In addition, CMPs can differentiate into monocyte dendritic cell (MDP)
progenitor cells, participate in myelogenesis, and differentiate into progenitor-derived
plasmacytoid dendritic cells (pDCs). common dendritic cell bodies (CDP) and common
monocyte-derived monocyte (cMoP) progenitor (MC) cells, which further differentiate into
monocyte-derived DC (mDC) and macrophages (M) (3).

3. NUCLEUS EXTRUSION

As erythrocytes progress through the stages of maturation, the nucleus undergoes significant
changes. During the early stages of erythroblast development, the nucleus is large and
prominent, containing the genetic material necessary for cell division and growth. However,
as red blood cells mature, they undergo a process known as chromatin condensation, in which
DNA is compacted and tightly packed. This condensation allows the nucleus to be expelled
from the cell, making room for the accumulation of hemoglobin and other components
essential for red blood cell functioning.
4. RETICULOCYTE MATURATION

After the nucleus is ejected, the red blood cells become reticulocytes. Reticulocytes are
immature red blood cells that still contain some residual organelles, especially ribosomes.
They are released from the bone marrow into the bloodstream to continue the maturation
process. The presence of ribosomes gives them their grid-like or reticulated appearance
upon staining, hence the name "reticulocytes".

5. CIRCULATION

After entering the bloodstream, reticulocytes undergo a further maturation process, which
includes the removal of residual ribosomes and other organelles. This maturation process
usually takes about 1-2 days in humans, but the exact time can vary depending on
individual factors, such as the body's need for red blood cells and the growth of red blood
cells. presence of growth factors and cytokines affecting erythropoiesis.

During the maturation of reticulocytes, the remaining ribosomes and organelles are
gradually broken down and recycled or expelled from the cell. As a result, the
reticulocytes lose their reticular shape and take on the characteristic appearance of mature
red blood cells. The most notable change is the loss of the nucleus, which is eventually
removed from the cell. The absence of a nucleus is an important adaptation that allows
mature red blood cells to take on a biconcave shape and maximize their oxygen-carrying
capacity.

When reticulocytes have completed maturation and lost their nucleus and organelles, they
become fully functional red blood cells, also known as mature erythrocytes. Mature red
blood cells specialize in transporting oxygen and their main function is to carry oxygen
from the lungs to the body's tissues and organs, and to help remove carbon dioxide for
exhalation. Their biconcave shape provides a larger surface area for gas exchange,
ensuring efficient oxygen absorption and release.
 6. COMMITMENT TO ERYTHROID LINEAGE
Diffuse myeloid progenitor cells are a type of multipotent progenitor cells derived from
disseminated myeloid progenitor cells (MPCs). CMPs are committed progenitor cells that
have lost some of the pluripotent properties of hematopoietic stem cells (HSCs) and are more
specialized in the myeloid lineage. These myeloid progenitor cells can give rise to various
myeloid cells, including granulocytes, monocytes, and erythrocytes (red blood cell
precursors).

Erythropoietin (EPO) is a hormone produced mainly by the kidneys in response to low blood
oxygen levels. When oxygen levels drop, EPO is released into the bloodstream and acts as a
signalling molecule needed for erythropoiesis, the process that makes red blood cells. EPO
binds to receptors on diffuse myeloid progenitor cells, inducing specific genetic programs
that promote their commitment to erythrocytosis.
DISEASES THAT AFFECT HEMATOPOEISIS

Several diseases can affect hematopoiesis, which is the process by which blood cells form
in the bone marrow. These conditions can disrupt the normal production, maturation, or
function of various types of blood cells, leading to a range of health problems. Some
diseases that affect hematopoiesis include:

Anemia:

Anemia is a common disorder characterized by a deficiency of red blood cells or hemoglobin

in the blood. It can have many causes, such as nutritional deficiencies (iron, vitamin B12, or
folate), chronic disease, genetic disorders (eg, thalassemia), or autoimmune disease.
Anemia reduces the blood's ability to carry oxygen, leading to fatigue, weakness, and other
symptoms.

Leukemia:

Leukemia is a type of cancer that starts in the bone marrow and affects the production of
white blood cells. This leads to an uncontrolled proliferation of abnormal white blood cells,
crowding out healthy blood cells and impairing normal hematopoiesis. There are different
types of leukemia, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia
(AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia ( CML).

Myelodysplastic syndrome (MDS):

MDS is a group of bone marrow disorders characterized by inefficient hematopoiesis and

abnormal cell maturation. In MDS, the bone marrow doesn't produce enough mature and
functional blood cells, leading to many blood-related problems, such as anemia,
neutropenia (low white blood cell count), and decreased blood pressure. platelets (low
platelet count).

Non-regenerative anemia:

Aplastic anemia is a rare but serious condition in which the bone marrow does not produce
enough of three types of blood cells: red blood cells, white blood cells, and platelets. It is
usually caused by an autoimmune reaction or exposure to certain drugs, chemicals, or
infections.
Vera polycythemia vera:

Primary polycythemia vera is a myeloproliferative tumor characterized by an

overproduction of red blood cells, white blood cells, and platelets. This leads to increased
total blood volume and thickening of the blood, increasing the risk of blood clots and
cardiovascular complications.

Thrombocytopenia:

Thrombocytopenia is a condition characterized by a low platelet count. It can be caused by

many factors, including immune-mediated destruction of platelets, bone marrow disorders,
infections, medications, and certain genetic conditions. Thrombocytopenia can lead to an
increased risk of bleeding and bruising.

Lymphocyte phagocytosis (HLH):

HLH is a rare and life-threatening disease in which the immune system becomes overactive,
leading to excessive inflammation and destruction of blood cells in the bone marrow. It can
be triggered by infections, certain autoimmune diseases, or malignancies.

These are just a few examples of diseases that can affect hematopoiesis. Many other
conditions, including certain infections, autoimmune diseases, and bone marrow
disorders, can also affect normal blood cell production and function. Proper diagnosis and
treatment are essential to manage these diseases and support hematopoiesis to ensure
adequate and functional blood cell production.
 CONCLUSION

In summary, the production of red blood cells is a very complex and tightly controlled
process, known as erythropoiesis. Hematopoietic stem cells (HSCs) play a central role in
this process, as they have the remarkable ability to differentiate into many types of blood
cells, including red blood cells. Under the influence of growth factors and cytokines,
HSCs differentiate into erythroid progenitor cells, which undergo several stages of
maturation, culminating in the formation of mature red blood cells.

Erythropoiesis is strictly controlled to ensure the proper balance of red blood cells in the
body. Erythropoietin (EPO), produced in response to low oxygen levels, is a key regulator
of erythropoiesis, stimulating the production and maturation of red blood cells in the bone
marrow. Nutritional factors, hormonal influences and many other signals also contribute
to the regulation of erythropoiesis.

The complex understanding of erythropoiesis and the role of hematopoietic stem cells in
the production of red blood cells has important implications for medical science. This
knowledge is essential for the diagnosis and management of various blood disorders, such
as anemia, and has led to advances in treatment and therapy for blood-related diseases. As
research into haematopoiesis continues, our understanding of this complex process is
likely to deepen, paving the way for new medical breakthroughs and better health care
outcomes for patients with various diseases. blood related. Finally, red blood cell
generation exemplifies the wonders of biological regulation, allowing the body to
maintain an efficient blood system to sustain life and ensuring an adequate supply of
oxygen to all tissues. and agency.
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• https://www.nature.com/articles/cddiscovery20172
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