ERYTHROPOIESIS: STAGES AND THEIR CHARACTERISTICS, REGULATION, STIMULANTS - BIOLOGY - 2025

The erythropoiesis is the process by which red blood cells or erythrocytes are formed. These blood cells, in humans, have an average life span of 4 months and are unable to reproduce themselves. Because of this, new erythrocytes must be created to replace those that die or are lost in hemorrhages.

In men, the number of red blood cells is approximately 54 million per milliliter, while in women it is slightly lower (48 million). About 10 million erythrocytes are lost daily, so a similar amount must be replaced.

Human blood, erythrocytes or red blood cells and two white blood cells. Taken and edited from: Viascos.

Erythrocytes are formed from nucleated erythroblasts present in the red bone marrow of mammals, while in other vertebrates they are produced mainly in the kidneys and spleen.

When they reach the end of their days, they fragment; then cells called macrophages encompass them. These macrophages are present in the liver, red bone marrow, and spleen.

When the red blood cells are destroyed, the iron is recycled to be used again, while the rest of the hemoglobin is transformed into a bile pigment called bilirubin.

Erythropoiesis is stimulated by a hormone called erythropoietin, but the process is regulated by different factors, such as temperature, oxygen pressure, among others.

Stages and their characteristics

In adult organisms, erythropoiesis occurs in specialized sites in the red bone marrow called erythroblastic islands. For the formation of erythrocytes, several processes must occur, ranging from cell proliferation to the maturation of red blood cells, passing through various stages of cell differentiation.

As cells undergo mitotic divisions, their size and that of their nucleus decrease, as well as chromatin condensation and hemoglobinization. Additionally, they are moving away from the area of ​​origin.

In the final stages they will lose the nucleus and other organelles and will enter into circulation, migrating through the cytoplasmic pores of endothelial cells.

Some authors divide the entire erythropoiesis process into two phases, the first of cell proliferation and differentiation; while others divide the process based on specific characteristics of the cell at each stage, when observed with Wright's stain. Based on the latter, the stages of erythropoiesis are:

1-Bursting colony forming units

They are the first cells sensitive to erythropoietin, some authors call them myeloid progenitors, or also BFU-E, for its acronym in English. They are characterized by expressing surface antigens such as CD34, as well as by the presence of erythropoietin receptors in low amounts.

2-Erythroid colony-forming cells

Abbreviated in English as CFU-E, they are capable of producing small colonies of erythroblasts. Another characteristic of these cells is that the amounts of erythropoietin receptors are much higher than in burst colony-forming units.

3-Proerythroblasts

Considered the first maturation stage of erythrocytes. They are characterized by their large size (14 to 19 µm according to some authors, up to 25 µm according to others). The nucleus is rounded and also presents nucleoli and abundant chromatin.

Considered the first maturation stage of erythrocytes. They are characterized by their large size (14 to 19 µm according to some authors, up to 25 µm according to others). The nucleus is large, rounded, with chromatin arranged in the form of filaments and 2 or 3 nucleoli.

In this stage, plasma iron uptake begins. They have a half-life of 20 hours, to give way through mitosis to the next stage.

4-Basophilic erythroblasts

Also called normoblasts, they are smaller than their precursors. These cells stain blue with vital staining, that is, they are basophilic. The nucleus is condensed, the nucleoli have disappeared and they have a large number of ribosomes. In this stage the synthesis of hemoglobin begins.

At the beginning they are known as Type I basophilic erythroblasts and after mitotic division they transform into Type II, which remain basophils and present greater hemoglobin synthesis. The approximate duration of both cells, together, is similar to that of proerythroblasts.

Hemoglobin. Taken and edited from: Zephyris at the English language Wikipedia.

5-polychromatophilic erythroblasts

They are formed by mitotic division of type II basophilic erythroblasts and are the last cells with the capacity to divide by mitosis. Their size ranges from 8 to 12 µm, and they have a rounded and condensed core.

The cytoplasm of these cells is stained lead gray with Wright's stain. It has a high concentration of hemoglobin and the number of ribosomes remains high.

6-Orthochromatic erythroblasts

The color of these cells is pink or red due to the amount of hemoglobin they have. Its size is slightly smaller than that of its precursors (7 to 10 µm) and it has a small nucleus, which will be expelled by exocytosis when the cells mature.

7-Reticulocytes

They are formed by differentiation of orthochromatic erythroblasts, lose organelles and fill their cytoplasm with hemoglobin. They remain in the red bone marrow for two to three days until they migrate to the blood where they will complete their maturation.

8-Erythrocytes

They are the mature formed elements, the end product of erythropoiesis and which are formed by the maturation of reticulocytes. They have a biconcave shape due to the absence of a nucleus and the interaction between the erythrocyte cytoskeleton and two proteins called spectrin and actin.

They are the most abundant blood cells, they are formed from reticulocytes. In mammals, they have a biconcave shape due to the absence of a nucleus and the interaction between the erythrocyte cytoskeleton and two proteins called spectrin and actin. In other vertebrates they are rounded and retain the nucleus.

Erythropoiesis process. Taken and edited from A.mikalauskas at the Lithuanian language Wikipedia

Regulation of erythropoiesis

Although erythropoietin stimulates the formation of red blood cells to improve the oxygen-carrying capacity of the blood, there are several fundamental mechanisms to regulate this formation, including:

Oxygen pressure

The concentration of oxygen in the blood regulates erythropoiesis. When this concentration is very low in the blood flow to the kidney, the production of red blood cells is stimulated.

This low concentration of tissue O2 can occur due to hypoxemia, anemia, renal ischemia or when the affinity of hemoglobin for this gas is higher than normal.

Miescher, in 1893, was the first to suggest the relationship between tissue hypoxia and erythropoiesis. However, this hypoxia does not directly stimulate the bone marrow to produce red blood cells, as Miescher suggested. Rather, it induces the kidney to produce the hormone erythropoietin.

Erythropoietin production due to tissue hypoxia is genetically regulated, and the receptors that detect such hypoxia are found within the kidney. Erythropoietin production is also increased due to a drop in tissue oxygen partial pressure following a hemorrhage.

The cells that make erythropoietin are found in the kidney and liver. The increase in the production of this hormone during anemia is due to an increase in the number of cells that produce it.

Testosterone

Testosterone indirectly regulates erythropoiesis, by regulating iron levels in the blood. This hormone acts directly on the action of a cytoplasmic protein called BMP-Smad (bone morphogenetic protein-Smad for its acronym in English) in hepatocytes.

Due to the action of testosterone, hepcidin transcription is suppressed. This hepcidin prevents the passage of iron from cells into plasma from macrophages that recycle iron, leading to a drastic decrease in blood iron.

When hypoferremia occurs there will be an inhibition of erythropoietin, as there will be no iron for the production of erythrocytes.

Temperature

Temperature has been shown to have an effect on erythripoiesis. Exposures to very low temperatures cause the need to produce heat in the fabrics.

This requires increasing the amount of erythrocytes in order to supply oxygen to peripheral tissues. However, it is not completely clear how this type of regulation occurs.

Paracrine regulation

Apparently, there is a production of erythropoietin by the neurons of the central nervous system, to protect themselves from ischemic damage and apoptosis. However, scientists have not been able to prove it yet.

Erythropoiesis stimulating agents

Erythropoiesis-stimulating agents (ESAs) are agents responsible for stimulating the production of erythrocytes. Erythropoietin is the hormone naturally in charge of this process, but there are also synthetic products with similar properties.

Erythropoietin is a hormone synthesized mainly in the kidney. During the early stages of development, the liver is also involved in the active production of erythropoietin. However, as development proceeds, the latter body plays less of a role in the process.

The erythrocyte begins to disperse receptors for erythropoietin on the membrane surface. Erythropoietin activates a series of intercellular signal transduction cascades that initially produce hemoglobin synthesis and cause reticulocytes to act more rapidly and be released into the circulation.

Artificial ESAs

Artificial ESAs are classified into generations (first to third), depending on the date they were created and marketed. They are structurally and functionally similar to erythropoietin.

The first generation ESAs are known as epoetin alpha, beta and delta. The first two are produced by recombination from animal cells and have a half-life of about 8 hours in the body. Epoetin delta, for its part, is synthesized from human cells.

Darbepoetin alfa is a second generation ESA, produced from Chinese hamster cells using technology called recombinant DNA. It has a half-life more than three times that of first-generation ESAs. As with epoetins, some high-performance athletes have used darbepoetin as a means of doping.

Continuous Erythropoetin Receptor Activator, or CERA for its acronym in English, is the generic name for third-generation ESAs. They do not attempt to simulate the structure and function of erythropoietin, but act by stimulating its receptor, thus increasing its effects.

Its half-life is several weeks instead of hours, like the previous drugs. Used commercially since 2008, however, its illicit use in sports activities apparently dates back two to three years before its legal commercialization.

Ineffective erythropoiesis

Ineffective or ineffective erythropoiesis occurs when the red blood cells formed are defective and are usually destroyed before or shortly after leaving the bone marrow.

Ineffective erythropoiesis may be due to defects in the synthesis of nucleic acids, the heme group, or globins. These defects cause different types of anemia.

Defects in nucleic acid synthesis

In this case, there is a deficiency of folic acid and cobalamin, the synthesis of DNA is inhibited in the nucleus of the cells that promote erythrocytes, so that they are unable to divide mitotically. The cytoplasm, for its part, does increase its volume (macrocytosis), originating a large cell called megaloblast.

In these cases, a series of anemias called megaloblastic anemias originate, of which the most common is pernicious anemia. In this disease there is no absorption of vitamin B12 in the small intestine.

Other causes of megaloblastic anemia include digestive diseases, malabsorption, folic acid deficiency, and due to certain medications.

Symptoms of this type of anemia include abnormal paleness, irritability, loss of appetite, diarrhea, difficulty walking, or muscle weakness. Depending on the cause, it can be treated with vitamin or folic acid supplements.

Defects in the synthesis of the heme group

Ineffective erythropoiesis due to deficiency in iron synthesis can cause two types of anemia; microcytic anemia due to iron deficiency and sideroblastic anemia.

Microcytic anemia is known as a group of anemias characterized by small and pale red blood cells, they can have different origins, including thalassemia and ineffective erythropoiesis.

In sideroblastic anemia, iron and hemosiderin levels are very high. Haemosiderin is a yellow pigment derived from hemoglobin and appears when levels of the metal are higher than normal. This type of anemia causes the death of basophils in the red bone marrow and there is no synthesis of hemoglobin.

Iron deficiency anemia. Taken and edited from: Erhabor Osaro (Associate Professor).

It is called sideroblastic anemia because the erythrocytes develop abnormally due to the accumulation of iron in the form of granules, receiving the name of sideroblasts. Sideroblastic anemia can be congenital or it can be secondary and have different causes.

Defects in globin synthesis

In this case, sickle cell anemia and beta thalassemia occur. Sickle cell anemia is also known as sickle cell anemia. It is produced by a genetic mutation that leads to the substitution of glutamic acid for valine during the synthesis of beta globin.

Due to this substitution, the affinity of hemoglobin for oxygen decreases and there is atrophy of the erythrocyte, acquiring a sickle shape instead of the normal biconcave disc shape. The patient with sickle cell anemia is susceptible to microinfarctions and hemolysis.

Thalassemia is a disease caused by an inadequate genetic coding of α- and β-globins that leads to early death of the erythrocyte. There are about a hundred different mutations that can cause thalassemia with varying degrees of severity.

References

1. Erithropoiesis. On Wikipedia. Recovered from en.wikipedia.org.
2. JP Labbrozzi (2015). Production of erythrocytes from umbilical cord blood CD34 ⁺ cells. Doctoral Thesis. Autonomous University of Barcelona. Spain.
3. H. Parrales (2018). Physiology of erythropoiesis. Recovered from cerebromedico.com.
4. Anemia. On Wikipedia. Recovered from en.wikipedia.org.
5. Erithropoiesis stimulating agent. On Wikipedia. Recovered from en.wikipedia.org.
6. Ineffective erithropoiesis. On Wikipedia. Recovered from en.wikipedia.org.