Erythropoiesis

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Haematopoiesis

Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. [2]

Contents

It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin. [3] This hormone stimulates proliferation and differentiation of red cell precursors, which activates increased erythropoiesis in the hemopoietic tissues, ultimately producing red blood cells (erythrocytes). [3] In postnatal birds and mammals (including humans), this usually occurs within the red bone marrow. [3] In the early fetus, erythropoiesis takes place in the mesodermal cells of the yolk sac. By the third or fourth month, erythropoiesis moves to the liver. [4] After seven months, erythropoiesis occurs in the bone marrow. Increased levels of physical activity can cause an increase in erythropoiesis. [5] However, in humans with certain diseases and in some animals, erythropoiesis also occurs outside the bone marrow, within the spleen or liver. This is termed extramedullary erythropoiesis .

The bone marrow of essentially all the bones produces red blood cells until a person is around five years old. The tibia and femur cease to be important sites of hematopoiesis by about age 25; the vertebrae, sternum, pelvis and ribs, and cranial bones continue to produce red blood cells throughout life. Up to the age of 20 years, RBCs are produced from red bone marrow of all the bones (long bones and all the flat bones). After the age of 20 years, RBCs are produced from membranous bones such as vertebrae, the sternum, ribs, scapulas, and the iliac bones. After 20 years of age, the shaft of the long bones becomes yellow bone marrow because of fat deposition and loses the erythropoietic function. [6]

Comparison of erythrocyte production by marrow stem cell lines from old and young adult donors shows no significant differences. [7] This finding implies that little or none of the proliferative capacity of the erythropoietic stem cells is exhausted by a lifetime of normal functioning. [7]

Erythrocyte differentiation

In the process of red blood corpuscle maturation, a cell undergoes a series of differentiations . The following stages of development all occur within the bone marrow:

  1. A hemocytoblast, a multipotent hematopoietic stem cell, becomes
  2. a common myeloid progenitor or a multipotent stem cell, then
  3. a unipotent stem cell, then
  4. a pronormoblast (also commonly called an proerythroblast or a rubriblast), then
  5. a basophilic or early normoblast (also commonly called an erythroblast), then
  6. a polychromatophilic or intermediate normoblast, then
  7. an orthochromatic or late normoblast. At this stage the nucleus is expelled before the cell becomes
  8. a reticulocyte. (These cells still contain RNA and are also called "immature red blood cells")

The cell is released from the bone marrow after Stage 7, and so in newly circulating red blood cells there are about 1% reticulocytes. After one to two days, these ultimately become "erythrocytes" or mature red blood cells.

These stages correspond to specific appearances of the cell when stained with Wright's stain and examined by light microscopy, and correspond to other biochemical changes.

In the process of maturation, a basophilic pronormoblast is converted from a cell with a large nucleus and a volume of 900 fL to an enucleated disc with a volume of 95 fL. By the reticulocyte stage, the cell has extruded its nucleus, but is still capable of producing hemoglobin.

Essential for the maturation of red blood cells are Vitamin B12 (cobalamin) and Vitamin B9 (folate). Lack of either causes maturation failure in the process of erythropoiesis, which manifests clinically as reticulocytopenia, an abnormally low amount of reticulocytes.

Characteristics seen in erythrocytes during erythropoiesis

As they mature, a number of erythrocyte characteristics change:

Mechanism of erythropoiesis

The production of all blood cells begins with the haemocytoblast, a multipotent haematopoietic stem cell. Haemocytoblasts have the greatest powers of self-renewal of any adult cell. They are found in the bone marrow and can be mobilised into the circulating blood when needed. Some haemocytoblasts differentiate into common myeloid progenitor cells, which go on to produce erythrocytes, as well as mast cells, megakaryocytes and myeloblasts. The process by which common myeloid progenitor cells become fully mature red blood cells involves several stages. First, they become normoblasts (aka eryhthroblasts), which are normally present in the bone marrow only. Then, they lose their nucleus as they mature into reticulocytes, which can be thought of as immature red blood cells. Some of these are released into the peripheral circulation. Finally, reticulocytes lose their remaining organelles as they mature into erythrocytes-which are fully mature red blood cells. The average lifespan of a red blood cell is approximately 120 days. During this maturation process, there is nuclear extrusion – i.e. mature erythrocytes have no nucleus. Nucleated red blood cells present in a sample of bone marrow can indicate the release of incompletely developed cells. This can occur in pathology such as thalassaemia, severe anaemia or haematological malignancy.

Regulation of erythropoiesis

A feedback loop involving erythropoietin helps regulate the process of erythropoiesis so that, in non-disease states, the production of red blood cells is equal to the destruction of red blood cells and the red blood cell number is sufficient to sustain adequate tissue oxygen levels but not so high as to cause sludging, thrombosis, or stroke. Erythropoietin is produced in the kidney and liver in response to low oxygen levels. In addition, erythropoietin is bound by circulating red blood cells; low circulating numbers lead to a relatively high level of unbound erythropoietin, which stimulates production in the bone marrow.

Recent studies have also shown that the peptide hormone hepcidin may play a role in the regulation of hemoglobin production, and thus affect erythropoiesis. The liver produces hepcidin. Hepcidin controls iron absorption in the gastrointestinal tract and iron release from reticuloendothelial tissue. Iron must be released from macrophages in the bone marrow to be incorporated into the heme group of hemoglobin in erythrocytes. There are colony forming units that the cells follow during their formation. These cells are referred to as the committed cells including the granulocyte monocyte colony forming units.

The secretion of hepcidin is inhibited by another hormone, erythroferrone, produced by erythroblasts in response to erythropoietin, and identified in 2014. [9] [10] It appears that this links erythropoietin-driven eyrthropoiesis with the iron mobilization needed for hemoglobin synthesis.

Loss of function of the erythropoietin receptor or JAK2 in mice cells causes failure in erythropoiesis, so production of red blood cells in embryos and growth is disrupted. If there is no systemic feedback inhibition, for example, the diminishment or absence of suppressors of cytokine signaling proteins, giantism may result as shown in mice models. [11] [12]

Stress erythropoiesis

In addition to the steady state erythropoiesis, acute anemia probably stimulates another response which results in rapid development of new red blood cells. This has been studied in rats and happens in the liver through the activation of the BMP4-dependent stress erythropoiesis pathway. [13]

See also

Related Research Articles

<span class="mw-page-title-main">Haematopoiesis</span> Formation of blood cellular components

Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten billion to a hundred billion new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.

<span class="mw-page-title-main">Red blood cell</span> Oxygen-delivering blood cell and the most common type of blood cell

Red blood cells (RBCs), scientific name erythrocytes (from Greek erythros 'red' and kytos 'hollow vessel', with -cyte translated as 'cell' in modern usage), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells) or haematids, are the most common type of blood cell and the vertebrate's principal means of delivering oxygen (O2) to the body tissues—via blood flow through the circulatory system. Erythrocytes take up oxygen in the lungs, or in fish the gills, and release it into tissues while squeezing through the body's capillaries.

<span class="mw-page-title-main">Blood cell</span> Cell produced by hematopoiesis

A blood cell, also called a hematopoietic cell, hemocyte, or hematocyte, is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), and platelets (thrombocytes). Together, these three kinds of blood cells add up to a total 45% of the blood tissue by volume, with the remaining 55% of the volume composed of plasma, the liquid component of blood.

<span class="mw-page-title-main">Erythropoietin</span> Protein that stimulates red blood cell production

Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease.

<span class="mw-page-title-main">Reticulocyte</span> Blood cells

Reticulocytes are immature red blood cells (RBCs). In the process of erythropoiesis, reticulocytes develop and mature in the bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells, in mammals, reticulocytes do not have a cell nucleus. They are called reticulocytes because of a reticular (mesh-like) network of ribosomal RNA that becomes visible under a microscope with certain stains such as new methylene blue and Romanowsky stain.

<span class="mw-page-title-main">Hereditary spherocytosis</span> Medical condition

Hereditary spherocytosis (HS) is a congenital hemolytic disorder, wherein a genetic mutation coding for a structural membrane protein phenotype leads to a spherical shaping of erythrocytic cellular morphology. As erythrocytes are sphere-shaped (spherocytosis), rather than the normal biconcave disk-shaped, their morphology interferes with these cells' abilities to be flexible during circulation throughout the entirety of the body - arteries, arterioles, capillaries, venules, veins, and organs. This difference in shape also makes the red blood cells more prone to rupture under osmotic and/or mechanical stress. Cells with these dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes resulting in hemolytic anemia.

<span class="mw-page-title-main">Megakaryocyte</span> Type of bone marrow cell

A megakaryocyte is a large bone marrow cell with a lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal clotting. In humans, megakaryocytes usually account for 1 out of 10,000 bone marrow cells, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte.

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells. As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.

<span class="mw-page-title-main">Sideroblastic anemia</span> Medical condition

Sideroblastic anemia, or sideroachrestic anemia, is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need in order to transport oxygen efficiently. The disorder may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can develop into hematological malignancies.

<span class="mw-page-title-main">Proerythroblast</span>

A proerythroblast is the earliest of four stages in development of the normoblast.

Reticulocytopenia is the medical term for an abnormal decrease in circulating red blood cell precursors (reticulocytes) that can lead to anemia due to resulting low red blood cell (erythrocyte) production. Reticulocytopenia may be an isolated finding or it may not be associated with abnormalities in other hematopoietic cell lineages such as those that produce white blood cells (leukocytes) or platelets (thrombocytes), a decrease in all three of these lineages is referred to as pancytopenia.

<span class="mw-page-title-main">Erythropoietin receptor</span> Protein-coding gene in the species Homo sapiens

The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the EPOR gene. EpoR is a 52kDa peptide with a single carbohydrate chain resulting in an approximately 56-57 kDa protein found on the surface of EPO responding cells. It is a member of the cytokine receptor family. EpoR pre-exists as dimers. These dimers were originally thought to be formed by extracellular domain interactions, however, it is now assumed that it is formed by interactions of the transmembrane domain and that the original structure of the extracellular interaction site was due to crystallisation conditions and does not depict the native conformation. Binding of a 30 kDa ligand erythropoietin (Epo), changes the receptor's conformational change, resulting in the autophosphorylation of Jak2 kinases that are pre-associated with the receptor. At present, the best-established function of EpoR is to promote proliferation and rescue of erythroid progenitors from apoptosis.

<span class="mw-page-title-main">HOXA9</span> Protein-coding gene in humans

Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.

The term macrocytic is from Greek words meaning "large cell". A macrocytic class of anemia is an anemia in which the red blood cells (erythrocytes) are larger than their normal volume. The normal erythrocyte volume in humans is about 80 to 100 femtoliters. In metric terms the size is given in equivalent cubic micrometers. The condition of having erythrocytes which are too large, is called macrocytosis. In contrast, in microcytic anemia, the erythrocytes are smaller than normal.

<span class="mw-page-title-main">CFU-GEMM</span>

CFU-GEMM is a colony forming unit that generates myeloid cells. CFU-GEMM cells are the oligopotential progenitor cells for myeloid cells; they are thus also called common myeloid progenitor cells or myeloid stem cells. "GEMM" stands for granulocyte, erythrocyte, monocyte, megakaryocyte.

<span class="mw-page-title-main">CFU-E</span>

CFU-E stands for Colony Forming Unit-Erythroid. It arises from CFU-GEMM and gives rise to proerythroblasts.

<span class="mw-page-title-main">Megakaryocyte–erythroid progenitor cell</span>

Megakaryocyte–erythroid progenitor cells, among other blood cells, are generated as a result of hematopoiesis, which occurs in the bone marrow. Hematopoietic stem cells can differentiate into one of two progenitor cells: the common lymphoid progenitor and the common myeloid progenitor. MEPs derive from the common myeloid progenitor lineage. Megakaryocyte/erythrocyte progenitor cells must commit to becoming either platelet-producing megakaryocytes via megakaryopoiesis or erythrocyte-producing erythroblasts via erythropoiesis. Most of the blood cells produced in the bone marrow during hematopoiesis come from megakaryocyte/erythrocyte progenitor cells.

<span class="mw-page-title-main">Haematopoietic system</span>

The haematopoietic system is the system in the body involved in the creation of the cells of blood.

<span class="mw-page-title-main">Nucleated red blood cell</span> Red blood cell with a cell nucleus

A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of these red blood cells are nucleated. In mammals, NRBCs occur in normal development as precursors to mature red blood cells in erythropoiesis, the process by which the body produces red blood cells.

<span class="mw-page-title-main">Erythroferrone</span>

Erythroferrone is a protein hormone encoded in humans by the ERFE gene. Erythroferrone is produced by erythroblasts, inhibits the production of hepcidin in the liver, and so increases the amount of iron available for hemoglobin synthesis. Skeletal muscle secreted ERFE has been shown to maintain systemic metabolic homeostasis.

References

  1. ↑ Le, Tao; Bhushan, Vikas; Vasan, Neil (2010). First Aid for the USMLE Step 1: 2010 20th Anniversary Edition. USA: The McGraw-Hill Companies, Inc. pp.  123. ISBN   978-0-07-163340-6.
  2. ↑ Pelley, John W. (2007-01-01). "Amino Acid and Heme Metabolism". Elsevier's Integrated Biochemistry. pp. 97–105. doi:10.1016/B978-0-323-03410-4.50018-3. ISBN   9780323034104. Erythropoiesis
    Heme synthesis is coordinated with globin synthesis during erythropoiesis and as such does not occur in the mature erythrocyte. Erythropoiesis is the development of mature red blood cells from erythropoietic stem cells. The first cell that is morphologically recognizable in the red cell pathway is the proerythroblast. In the basophilic erythroblast, the nucleus becomes somewhat smaller, exhibiting a coarser appearance, and the cytoplasm becomes more basophilic owing to the presence of ribosomes. As the cell begins to produce hemoglobin, the cytoplasm attracts both basic and eosin stains and is called a polychromatophilic erythroblast. As maturation continues, the orthochromatophilic erythroblast extrudes its nucleus and the cell enters the circulation as a reticulocyte. As reticulocytes lose their polyribosomes, they become mature red blood cells.
  3. 1 2 3 Sherwood, L, Klansman, H, Yancey, P: Animal Physiology, Brooks/Cole, Cengage Learning, 2005.
  4. ↑ Palis J, Segel GB (June 1998). "Developmental biology of erythropoiesis". Blood Rev. 12 (2): 106–14. doi:10.1016/S0268-960X(98)90022-4. PMID   9661799.
  5. ↑ Le, Tao; Bhushan, Vikas; Vasan, Neil (2010). First Aid for the USMLE Step 1: 2010 20th Anniversary Edition. USA: The McGraw-Hill Companies, Inc. pp.  124. ISBN   978-0-07-163340-6.
  6. ↑ Sembulingam, K.; Sembulingam, Prema (2012-09-30). Essentials of Medical Physiology. JP Medical Ltd. p. 71. ISBN   978-93-5025-936-8.
  7. 1 2 Harrison, David E. (1979). "Proliferative capacity of erythropoietic stem cell lines and aging: An overview". Mechanisms of Ageing and Development. 9 (5–6): 409–426. doi:10.1016/0047-6374(79)90082-4. PMID   37376. S2CID   31601624.
  8. ↑ Textbook of Physiology by Dr. A. K. Jain reprint 2006-2007 3rd edition.
  9. ↑ Koury, M.J. (2015-01-13). "Erythroferrone: A Missing Link in Iron Regulation". The Hematologist. American Society of Hematology. Archived from the original on 2019-01-28. Retrieved 26 August 2015.
  10. ↑ Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T (Jul 2014). "Identification of erythroferrone as an erythroid regulator of iron metabolism". Nature Genetics. 46 (7): 678–84. doi:10.1038/ng.2996. PMC   4104984 . PMID   24880340.
  11. ↑ Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, Sirito M, Sawadogo M, Kahn A, Vaulont S (April 2002). "Severe iron deficiency anemia in transgenic mice expressing liver hepcidin". Proc. Natl. Acad. Sci. U.S.A. 99 (7): 4596–601. Bibcode:2002PNAS...99.4596N. doi: 10.1073/pnas.072632499 . PMC   123693 . PMID   11930010.
  12. ↑ Michael Föller; Stephan M. Huber; Florian Lang (August 2008). "Erythrocyte programmed cell death". IUBMB Life. 60 (10): 661–668. doi: 10.1002/iub.106 . PMID   18720418. S2CID   41603762.[ dead link ]
  13. ↑ Paulson, Robert F.; Shi, Lei; Wu, Dai-Chen (May 2011). "Stress erythropoiesis: new signals and new stress progenitor cells". Current Opinion in Hematology. 18 (3): 139–145. doi:10.1097/MOH.0b013e32834521c8. ISSN   1065-6251. PMC   3099455 . PMID   21372709.
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