Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...

s (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. It is stimulated by decreased O₂ in circulation, which is detected by the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

s, which then secrete the hormone

erythropoietin Erythropoietin (; EPO), 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 th ...

.Sherwood, L, Klansman, H, Yancey, P: ''Animal Physiology'', Brooks/Cole, Cengage Learning, 2005. This hormone stimulates proliferation and differentiation of red cell precursors, which activates increased erythropoiesis in the hemopoietic tissues, ultimately producing

red blood cells Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...

(erythrocytes). In postnatal

bird Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweig ...

s and

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur ...

s (including

humans" \n\n\n\n\nThe robots exclusion standard, also known as the robots exclusion protocol or simply robots.txt, is a standard used by websites to indicate to visiting web crawlers and other web robots which portions of the site they are allowed to visi ...

), this usually occurs within the

red bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic c ...

. In the early

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...

, erythropoiesis takes place in the mesodermal cells of the

yolk sac The yolk sac is a membranous wikt:sac, sac attached to an embryo, formed by cells of the hypoblast layer of the bilaminar embryonic disc. This is alternatively called the umbilical vesicle by the Terminologia Embryologica (TE), though ''yolk sac' ...

. By the third or fourth month, erythropoiesis moves to the liver. After seven months, erythropoiesis occurs in the bone marrow. Increased levels of physical activity can cause an increase in erythropoiesis. However, in

with certain

diseases A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

and in some

animals Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...

, erythropoiesis also occurs outside the

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

, within the

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

. This is termed '' extramedullary erythropoiesis''. The

of essentially all the

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

s produces red blood cells until a person is around five

years A year or annus is the orbital period of a planetary body, for example, the Earth, moving in its orbit around the Sun. Due to the Earth's axial tilt, the course of a year sees the passing of the seasons, marked by change in weather, the hou ...

old. The

tibia The tibia (; ), also known as the shinbone or shankbone, is the larger, stronger, and anterior (frontal) of the two bones in the leg below the knee in vertebrates (the other being the fibula, behind and to the outside of the tibia); it conn ...

and

femur The femur (; ), or thigh bone, is the proximal bone of the hindlimb in tetrapod vertebrates. The head of the femur articulates with the acetabulum in the pelvic bone forming the hip joint, while the distal part of the femur articulates ...

cease to be important sites of hematopoiesis by about age 25; the

vertebra The spinal column, a defining synapomorphy shared by nearly all vertebrates, Hagfish are believed to have secondarily lost their spinal column is a moderately flexible series of vertebrae (singular vertebra), each constituting a characteristi ...

e, sternum,

pelvis The pelvis (plural pelves or pelvises) is the lower part of the trunk, between the abdomen and the thighs (sometimes also called pelvic region), together with its embedded skeleton (sometimes also called bony pelvis, or pelvic skeleton). The ...

and

rib In vertebrate anatomy, ribs ( la, costae) are the long curved bones which form the rib cage, part of the axial skeleton. In most tetrapods, ribs surround the chest, enabling the lungs to expand and thus facilitate breathing by expanding the ches ...

s, 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. Comparison of erythrocyte production by marrow stem cell lines from old and young adult donors shows no significant differences.Harrison DE. Proliferative capacity of erythropoietic stem cell lines and aging: an overview. Mech Ageing Dev. 1979 Mar;9(5-6):409-26. doi: 10.1016/0047-6374(79)90082-4. PMID: 37376 This finding implies that little or none of the proliferative capacity of the erythropoietic stem cells is exhausted by a lifetime of normal functioning.

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

: # A

hemocytoblast Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...

, a

multipotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...

hematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cell ...

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...

, becomes # a common myeloid progenitor or a multipotent stem cell, then # a unipotent stem cell, then # a pronormoblast (also commonly called an proerythroblast or a rubriblast), then # a basophilic or early normoblast (also commonly called an erythroblast), then # a polychromatophilic or intermediate normoblast, then # an orthochromatic or late normoblast. At this stage the nucleus is expelled before the cell becomes # 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 Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: * Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

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 Reticulocytopenia is the medical term for an abnormal decrease of reticulocytes in the body. Reticulocytes are new, immature red blood cells. Causes Reticulocytopenia is usually a result of viral parvovirus B19 infection, which invades and destr ...

, an abnormally low amount of reticulocytes.

Characteristics seen in erythrocytes during erythropoiesis

As they mature, a number of erythrocyte characteristics change: * The overall size of the erythroid precursor cell decreases, increasing the cytoplasmic to nucleus (C:N) ratio. The nuclear diameter decreases and chromatin condenses with the staining reaction progressing from purplish red to dark blue at the final nuclear stage of the orthochromatic erythroblast, prior to nuclear ejection. * The colour of the cytoplasm changes from blue at proerythroblast and basophilic stages to a pinkish red as a result of the increasing expression of haemoglobin as the cell develops. * The nucleus is initially large in size and contains open

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...

. As red blood cells mature, the size of the nucleus decreases, until it finally disappears with the condensation of the chromatin material.

Regulation of erythropoiesis

A feedback loop involving

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 Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (th ...

, or

stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...

. 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 Hepcidin is a protein that in humans is encoded by the ''HAMP'' gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals. During conditions in which the hepcidin level is abnormally high, such as inflammation, s ...

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 Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

in the bone marrow to be incorporated into the heme group of

hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythroc ...

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. 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 Gigantism ( el, γίγας, ''gígas'', "giant", plural γίγαντες, ''gígantes''), also known as giantism, is a condition characterized by excessive growth and height significantly above average. In humans, this condition is caused by ove ...

may result as shown in

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...

models.

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.

References

External links