HEMATOPOIESIS
Definition
The cellular
part of blood consists of: White Blood Cells (WBC), Red Blood Cells (RBC),
and platelets (plt).
Hematopoiesis is the process of making new blood cells (of any
type). Hematopoiesis occurs in a
specialized organ (or system) known as the hematopoietic organ, which consists
of:
1-
The Bone Marrow (BM), the most important.
2-
The spleen and liver.
3-
The lymphatic tissue, such as lymph nodes, tonsils,
thymus, etc.
4-
The kidneys.
5-
The vascular endothelial system (arteries, veins, blood
vessels, etc.).
Hematopoietic development
During
embryogenesis, the yolk sac is main source of hematopoiesis for the
first 3 month (producing, RBC mainly).
The liver and spleen start producing blood from the 6th week,
reaching their maximum capacity at 5 month, after which their production of
blood cells start to decline. By the 9th
month (just before birth), the liver and spleen production becomes
minimum. The BM starts its production by
the 4th month and reaches its maximum by birth. In other words, by birth, only the BM is
the single organ responsible about Hematopoiesis (and continues through out the
whole life).
During
adult life, until the age of 20 years, the bone marrows of tibia
and femur are responsible about the production of the majority of blood
cells. The bone marrows of ribs,
sternum, and vertebra continue to produce blood cells until the very late
stages of life. The BM of all bones
usually is predominated with RED marrow in the young age (e.g., > 55% in
babies) but it gets replaced by YELLOW marrow as age progresses (< 35% red
marrow in people over 80 years old). Red
marrow consists of mainly hematopoietic cells where as yellow marrow consists
of non-hematopoietic cells, e.g., fibroblasts, fat cells, reticulo-endothelial
cells, etc.
BM structure
The sinuses that branch through
the hematopoietic tissue (or space) are made of a very thin layer of
endothelial cells separated by apertures. Hematopoietic cells pass through
these apertures to the sinuses, and then freely pour into the central vein to
take them to peripheral blood (see diagram, below).
Components of
hematopoiesis
The hematopoietic system cannot operate without the
presence of normally functioning three components:
1- Stem Cells
2- Growth Factors (GF's)
3- Hematopoietic Inductive Micro-environment (HIM)
1- THE STEM CELL
It is probably the most important factor in
hematopoiesis. Stem cells are the basis
of many treatments of leukemia.
Definition
The stem cell is
defined as a very primitive cell, which is capable, on its own, of giving
rise to all hematopoietic tissue.
The cell is primitive because it has not acquired any specific
markers of the specialized cell (e.g., netrophil, lymphocyte, red blood
cell, etc.). Usually, stem cells are
dormant or quiescent (resting), i.e., it is not engaged in any biological
activities except those needed for its survival. However, once needed, the cell can proliferate,
differentiate, or apoptose (see diagram enclosed).
Proliferation
is the term used to describe the ability of the stem cell to give rise to
“daughter” cells identical to the mother cell.
In other words, proliferation is a process in which stem cells can
increase their own numbers, i.e., re-producing themselves (also referred to as
"self-renewal").
Differentiation
is a process where stem cells start to acquire specific characters (usually
functional qualities) of a certain cell (or cell line) whether, lymphoid,
myeloid, or erythroid, etc. In other
words, the cells start to commit to become one of the mature blood cells.
Apoptosis
also known as “Programmed Cell Death” is a process where stem cells choose to
end their life (commit suicide). This
fate is chosen by the stem cells, if the environment was not favoring their
survival (e.g., decreased nutrients), or in the presence of an internal genetic
problem, e.g., mutation, deletion, translocation, etc.
Types of stem cells
Depending on the stage of
differentiation, stem cells are classified into two types: the pluripotent
(toti-potent) stem cell and the multi-potent ones.
The
pluripotent (toti-potent) stem cell is the most primitive stem cell,
i.e., it has not committed it self to any particular cell
differentiation. In other words, this
cell can differentiate to become any of the hematological cells (i.e., RBC,
WBC, or plts). In general, most studies
and literature refer to this cell as the “stem cell” without specifying the
pluripotent status. The cells are also
known as CD 34+ due to their possession of CD 34. They are also known as CFU-S (Colony Forming
Unit-spleen) because they were found in the spleen of BM transplanted mice and
rats. These cells are rarely found in
the BM or peripheral blood (pb) and estimated to at 1 in more than 10,000
(1/10,000) nucleated WBC in the BM.
The
multi-potent stem cell has acquired some criteria (or characters) of
one of the blood cell lines (e.g., lymphoid, myeloid, or erythroid). This process is acquired through
differentiation, and once the stem cell has differentiated to a certain cell
lineage, it remains “committed” to that lineage. For instance, if a stem cell decided to
differentiate into neutrophils, then it has to commit it self to
differentiation down the myeloid series (more specifically, the granuloid one)
until it becomes a neutrophil.
Furthermore, once a stem cell has committed it self to a certain
lineage, it cannot revert back to its “un-committed” status neither it
can switch to another series (or cell lineage). That is, once it acquired some of the myeloid
characters (markers) it cannot become lymphoid.
These cells are known as the CFU-mix or CFU-GEMM for
Colony Forming Unit-mixture (mix) or colony forming unit-Granulocyte,
Erythrocyte, Monocyte, Megakaryocyte (GEMM), respectively.
2- GROWTH FACTORS (GF's)
Also known as
“Cytokines”, the growth factors are glycoprotein macromolecules (mostly) with
different biological functions. The
majority has a molecular weight of about 50 KDa (Killo-Dalton), or about 150
amino acids. Synthesized by
hematological and non-hematological tissues, GF’s act on all types of stem
cells (and mature cells, too) ending in a special effect on their target cell(s). For example, some growth factors are
essential for stem cell survival, while others are essential for stem cell
differentiation. Meanwhile, some
growth factors are crucial for stem cell proliferation, while certain growth
factors promote apoptosis.
Furthermore, the action is not only restricted to immature (stem) cells
but it extends to mature cells as well, where the acquisition of certain
“functional” qualities would not be achieved without the exposure to certain
growth factors. The interleukins (IL)
comprise the majority of GF, some of which include IL-1, IL-2, IL-3, IL-7,
IL-10, etc. The other major group is
known as the Colony Stimulating Factors (CSF’s). These include GM-CSF, G-CSF, and M-CSF
representing (and acting on) Granulocyte/Macrophage lineage, Granulocyte alone,
and Macrophage (monocyte), respectively.
The majority of GF’s work on more than one cell type (lineage). These are known as multi-lineage GF's such
as: IL-3, and SCF (Stem Cell Factor). On
the other hand, GF’s such as Erythropoietin (EPO), G-CSF, and M-CSF are
specialized GF’s with each one working only on one cell line, i.e.,
EPO for eythroid, G-CSF for granuloid, and M-CSF for monocytoid lineage.
Mechanism of action
Growth factors
have receptors on their target cell(s).
Once the receptor is bound to the growth factor, a cascade of gene
transcription is initiated ending in the synthesis (or inhibition) of a certain
product (protein). In the case of stem
cell proliferation, once a GF is bound to the surface receptor, a cascade of
gene transcription involved in cell cycle is started forcing the cell to
enter the “active cell cycle” (which ends in mitosis) and cell division occurs
leading to two daughter cells. GF’s also
have receptors in mature cells (even though they do not divide), however, the
activation of certain receptors by GF’s leads to the acquisition of new functional
characteristics (e.g., new enzyme, removal of an older enzyme, or protein,
etc.).
3- THE
MICRO-ENVIRONMENT
The Hematopoietic Inductive
Micro-environment (HIM) is commonly known as the “stroma”. It is described as the actual surroundings
of the hematopoietic cells in the BM. It
consists of all the types of blood cells along with non hematopoietic cells
that occupy the BM such as: fat cells (adipocytes or adipose tissue),
fibroblasts, endothelial cells, blood vessels, nerves and nerves endings, as
well as all the types of blood cells (mature and immature). These cells together form a crucial part of
hematopoiesis due to their secretion (release) of growth factors. Most malignant disorders (leukemia) are
associated with a defective stem cell, however, in a few cases of other malignant
disorders, the stem cell is intact but the stroma is defective. Such diseases are usually harder to treat due
to the fact that even Bone Marrow Transplant, (BMT), which is a source of
healthy stem cells, would not cure the problem.
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