Red blood cells: differentiation and synthesis
Most red blood cells are produced in membrane bones such as the spine, the sternum, the ribs, and the pelvis. Even these bones decrease production as age increases.
Place of production of red blood cells in the body
During the early weeks of embryonic development, nucleated erythrocytes are produced in the yolk sac. In the mid-trimester, the liver is the main organ that produces red blood cells, but a moderate number of red blood cells are also produced in the spleen and lymph nodes. Then, around the equivalent of the last month of pregnancy and after birth, red blood cells are made solely in the bone marrow.
In the picture, the bone marrow of the bones mainly produces red blood cells until the age of 5 years. The marrow of the long bones, except for the proximal ends of the brachial and tibia, becomes fat accumulating and does not produce red blood cells after 20 years of age. Over this age, most red blood cells are produced in membrane bones such as the spine, sternum, ribs, and pelvis. Even these bones decrease production as age increases.
Figure. The relative production rate of erythrocytes in the bone marrow differs at different ages.
Starting to synthesize blood cells
Pluripotent hematopoietic stem cells, growth and differentiation hormones. Blood cells come from the bone marrow from a simple type of cell called Universal Hematopoietic Stem Cell, which is where all the cells of circulating blood come from. The figure shows the successive division of pluripotent cells that make up the various cells of the circulatory system. As these cells reproduce, a small percentage of pluripotent cells are retained in the bone marrow to maintain the supply of blood cells to the circulatory system, although this number also decreases with age. However, most of the cells that are produced go on to differentiate to produce the remaining cell types to the right of the figure. Intermediate cells are very similar to pluripotent stem cells, although they are completely becoming a separate cell line and are called stem cells (CSCs).
Figure. Formation of various blood cells from primary pluripotent hematopoietic stem cells in the bone marrow.
Different stem cells, when cultured, produce separate clusters of blood cells. A stem cell that produces red blood cells is called colony-forming unit-erythrocyte (CFU-E) for short. Likewise, the Agranulocyte and Monoclonal WBC Cluster Unit is also abbreviated CFU-GM and so on for other clusters.
The growth and reproduction of various stem cells are controlled by many proteins called growth inducers. At least four major growth hormones have been described, each with different characteristics. One of them is interleukin-3, which stimulates the growth and reproduction of almost all different stem cells, while the other stimulates the growth of only a few types of cells.
Growth hormones stimulate growth but do not differentiate cells, but rather the function of another set of proteins called differentiation inducers. Each of these hormones differentiated only one type of stem cell that differentiated one or more steps into the final adult blood cell.
The formation of differentiating and growth hormones is controlled by factors outside the bone marrow. For example, with red blood cells, a lack of oxygen in the blood over a long period of time causes the stimulation, differentiation and production of large numbers of red blood cells, discussed later in this chapter. In the case of certain white blood cells, infectious diseases induce growth and differentiation, forming the last few types of white blood cells required to fight each individual agent.
Different stages of erythrocytes
The first cytoplasm that can be identified to belong to that red blood cell line is proerythroblast, as shown at the starting point of the figure. Under the right stimulation, a large number of these cells are formed from CFU-E cells.
When formed, the erythrocyte progenitor continues to divide several times, eventually producing more mature red blood cells. The first generation of cells was called basophil erythroblasts because they captured the primary dye colour; at this point, the cell has accumulated a very small amount of haemoglobin. In the next generation, as shown in the picture, cells are filled with haemoglobin to 34%, the nucleus coagulates, the remainder is eventually absorbed or removed from that cell. At the same time, the endoplasmic reticulum is also reabsorbed. The cell at this stage is called reticulocyte because there is still a small amount of the base-loving substance that is the remains of the Golgi apparatus, mitochondria, and a few other organelles of the cytoplasm. In this stage of reticulocytes, the cells travel from the bone marrow to the blood capillaries by Transvasation (through the fissures of the capillary membrane).
Figure. The origin of normal red blood cells (RBCs) and red blood cell characteristics in ischemic types.
The rest of the base-loving matter in reticulocytes usually disappears after 1-2 days to become mature red blood cells. Due to their short life, reticulocytes make up less than 1% of the total number of red blood cells in the blood.
Erythropoietin regulates red blood cell production
The total volume of red blood cells in the blood is adjusted to a narrow limit, and therefore (1) an adequate amount of red blood cells always ensures adequate oxygen transport from the lungs to the tissues, and (2) not becoming too much can interfere with blood flow. This control mechanism is diagrammed in the figure and is described in the following sections.
Tissue oxidation is the most essential regulatory factor in red blood cell production. In cases where the amount of oxygen transported to the tissue is reduced, the production of red blood cells is often increased. Therefore, when a person has a lot of anaemia, possibly due to a haemorrhage or another cause, the bone marrow produces large numbers of red blood cells. Also, the destruction of most of the bone marrow, especially by X-rays, causes the overproduction of the remaining bone marrow to supply enough red blood cells to the body.
Figure. The function of erythropoietin to increase red blood cell production when tissue oxidation decreases.
At high altitudes, the amount of oxygen in the air is greatly reduced, and insufficient oxygen supply to the tissue increases red blood cell production. In this case, the factor that controls red blood cell production is not the concentration of red blood cells in the blood, but the need for tissue oxygen.
Many diseases of the circulatory system that reduce blood flow in the tissues, especially those that cause a decrease in oxygen uptake by the blood flow as it travels through the lungs, can increase red blood cell production. This is quite typical in heart failure and many lung diseases because the lack of oxygen from these diseases increases the production of red blood cells, and thereby haematocrit and total blood volume.
Erythropoietin stimulates the production of red blood cells and they increase in the absence of oxygen
The main stimulus for red blood cell production in the absence of oxygen is a circulating hormone called erythropoietin, a glycoprotein with a molecular weight of about 34000. In the absence of erythropoietin, lack of oxygen will have little or no stimulation of red blood cell production. However, when the erythropoietin system is normal, the lack of oxygen significantly increases erythropoietin production, thereby increasing erythropoietin production until the oxygen demand is satisfied.
Erythropoietin is produced mainly in the kidneys. Normally, about 90% of erythropoietin is produced by the kidneys, the remainder mainly in the liver. It is unclear exactly where it is produced in the kidneys. Some studies have suggested that erythropoietin is produced by intercellular fibroblast-like cells that surround tubes in the outer shell and medulla regions where there is a high demand for oxygen. And perhaps other cells, including renal epithelial cells, also secrete erythropoietin in response to lack of oxygen.
Renal tissue anaemia leads to increased levels of the hypoxia Inducible Factor (HIF-1: hypoxia-inducible factor-1) in the tissue, as a transcription factor for a large number of oxygen deficiency inducers, including the erythropoietin gene. HIF-1 binds to the oxygen-deficient responders on the erythropoietin gene, including mRNA synthesis and ultimately increases erythropoietin synthesis.
Sometimes, non-renal anaemia stimulates the kidney to secrete erythropoietin, which suggests that an extra-renal receptor sends signals to the kidneys to produce this hormone. In particular, both norepinephrine and epinephrine and many other prostaglandins also stimulate erythropoietin synthesis.
When both kidneys are removed or they are damaged by kidney disease, the person will become severely anaemic because the remaining 10% of erythropoietin produced in other tissues (mainly in the liver) can only satisfy 1 / 3 to 1/2 of the oxygen synthesis the body needs.
Erythropoietin stimulates the production of erythrocyte progenitors from severe haemophilia stem cells. When in an oxygen-deficient environment, erythropoietin is produced within minutes to hours and peaks after 24 hours. However, no new red blood cells appear in the blood within 5 days. Since then, also from other studies, it has been confirmed that the important effect of erythropoietin is to stimulate the production of erythropoietin from pluripotent hematopoietic stem cells in the bone marrow. In addition, after the production of many erythroblasts, it accelerates the subsequent stages of erythrocytes and rapidly produces erythrocytes. This rapid production will continue while in an oxygen-deficient state or until sufficient red blood cell production is produced to carry enough oxygen to the tissue despite low air oxygen levels; now,
In the absence of erythropoietin, fewer red blood cells are synthesized by the bone marrow. At the other extreme, if there is a lot of erythropoietin, enough iron and other nutrients, the production of red blood cells can increase 10 times or more than normal. Hence, erythropoietin is a powerful control mechanism for erythropoietin synthesis.
RBC maturation requires vitamin B12 (Cyanocobalamin) and Folic Acid
Due to the need to continue to fill red blood cells, red blood cells are the fastest growing and reproductive cells in the body. Therefore, their maturity and fertility are highly dependent on the body's diet.
Particularly important for the final maturity of red blood cells are 2 vitamins, vitamin B12 and folic acid. Both are essential for DNA synthesis, as each vitamin is in a different way, required for the synthesis of thymidine triphosphate, one of the basic units that make up DNA. Therefore, a lack of vitamin B12 as well as folic acid will produce abnormal or deficient DNA, and lead to errors in the maturation of the nucleus and cell division. In addition, erythrocytes not only fail to proliferate rapidly, but also produce cells that are larger than normal red blood cells and are called macrocytes, which have the unstable membrane that is normally present. oval large disproportionate instead of normal 2-sided concave disc. These cells, when entering the general circulation, are still capable of carrying oxygen but have a short life due to fragility, equal to 1/2 to 1/3 of normal. So,
Maturation Failure (MF) is caused due to lack of absorption of vitamin B12 in the gastrointestinal tract - Malignant anaemia. A common cause of malignant anaemia is decreased absorption of vitamin B12 in the gastrointestinal tract, usually due to atrophy of the gastric mucosa, reducing gastric juice secretion. The parietal cells of the stomach produce a glycoprotein called an endogenous factor, which binds to vitamin B12 in food and can be absorbed by the intestines. The mechanism is as follows:
Internal factors are closely related to vitamin B12. Protect vitamins from being digested by gastric juice.
During binding, the endogenous factor binds to a specific receptor on the brush basil cell membrane of the ileum.
Vitamin B12 is introduced into the bloodstream for a few hours by the hydration of both the internal factor and the membrane vitamin.
Lack of internal factor reduces vitamin B12 due to decreased absorption. When vitamin B12 is absorbed into the bloodstream, it is first stored in large amounts in the liver and released slowly according to the needs of the bone marrow. The smallest amount of vitamin B12 needed to maintain the normal maturation of red blood cells per day is about 1-3 micrograms, and the amount stored in the liver and other tissues is about 1000 times this amount. Therefore, reducing the absorption of vitamin B12 in 3-4 years usually leads to anaemia caused by MF.
MF due to a lack of folic acid (pteroylglutamic acid). Folic acid is commonly found in many green vegetables, fruits, and meats (especially in the liver). However, it is easily destroyed when cooked. Likewise, people with an absorption disorder, such as a commonly diagnosed small bowel disease called sprue, often severely interfere with the absorption of both vitamin B12 and folic acid. Therefore, in many cases of MF anaemia, the cause is decreased absorption of both folic acid and vitamin B12 in the intestine.