HEMATOPOIESIS

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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 6^th week, reaching their maximum capacity at 5 month, after which their production of blood cells start to decline.  By the 9^th month (just before birth), the liver and spleen production becomes minimum.  The BM starts its production by the 4^th 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.