Erythropoiesis

Erythropoiesis is the process by which red blood cells (erythrocytes) are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin. This hormone stimulates proliferation and differentiation of red cell precursors, which activates increased erythropoiesis in the hemopoietic tissues, ultimately producing red blood cells. In postnatal birds and mammals (including humans), this usually occurs within the red bone marrow. 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 spleen and liver. After seven months, erythropoiesis occurs in the bone marrow. Decreased level of physical activity can cause an increase in erythropoiesis. 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 RBCs 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.

Erythrocyte differentiation
In the process of red blood cell maturation, a cell undergoes a series of differentiations. The following stages 1–7 of development all occur within the bone marrow:
 * 1) hemocytoblast a pluripotent hematopoietic stem cell
 * 2) Common myeloid progenitor multipotent stem cell
 * 3) unipotent stem cell
 * 4) pronormoblast also commonly called proerythroblast or rubriblast.
 * 5) basophilic normoblast/early normoblast also commonly called erythroblast
 * 6) polychromatophilic normoblast/intermediate normoblast
 * 7) orthochromatic normoblast/late normoblast - Nucleus is Expelled before becoming a reticulocyte
 * 8) reticulocyte

The cell is released from the bone marrow after stage 7, and so of circulating red blood cells there are ~1% reticulocytes. After 1–2 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, but 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.

Essentially important for the maturation of RBC'S are two vitamins B-12 and folic acid. Lack of any one of these 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
The following characteristics can be seen changing in the erythrocytes when they are maturing:
 * They show a reduction in the cell size;
 * The cytoplasmic matrix increases in amount;
 * Staining reaction of the cytoplasm changes from basophilic to acidophilic (this is because of the decrease in the amount of RNA and DNA);
 * Initially the nucleus was large in size and contained open chromatin. But with the maturation of RBC's the size of the nucleus decreases and finally disappears with the condensation of the chromatin material.

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

Also, 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.

Also, if there is no feedback inhibition, such as SOCS (Suppressors of Cytokine Signaling) proteins in the system, that would cause giantism in mice.