Erythropoiesis

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 (erythrocytes). 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 liver. After seven months, erythropoiesis occurs in the bone marrow. Increased levels 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 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.

Comparison of erythrocyte production by marrow stem cell lines from old and young adult donors shows no significant differences. 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 cell maturation, a cell undergoes a series of differentiations. The following stages of development all occur within the bone marrow:

1. The process begins with a hemocytoblast, also known as a multipotent hematopoietic stem cell. These cells regenerate independently, and the process at which they decide to commit to becoming a red blood cell over another type of blood cell is thought to be regulated by transcription factors that activate the genes necessary to become a red blood cell.
2. The hemocytoblast then becomes a multipotent progenitor cell.
3. The multipotent progenitor cell can either become a common myeloid progenitor (CMP) or a common lymphoid progenitor (CLP). CMPs are the cells that go on to become red blood cells as well as platelets, macrophages, monocytes, and granulocytes.
4. The common myeloid progenitor becomes a megakaryocyte/erythrocyte progenitor (MEP), which is the cell line that goes on to become red blood cells or platelets.
5. The first red blood cell precursor in the process of erythropoiesis is the pronormoblast (also commonly called a proerythroblast or a rubriblast). These are the largest of all the red blood cell precursors as the following cells decrease in size due to mitosis.
6. The pronormoblast becomes the basophilic or early normoblast (also commonly called an erythroblast).
7. The basopihilic normoblast becomes the polychromatophilic or intermediate normoblast.
8. This step marks the last stage of division, which leads to the formation of the orthochromatic or late normoblast.
9. At this stage the nucleus is expelled to form the reticulocyte. (These cells still contain RNA and are also called "immature red blood cells").

The cell is released from the bone marrow after Stage 8, 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). Cobalamin and folate are necessary for DNA synthesis, and deficiencies in either can impede mitosis, thus causing maturation failure in the process of erythropoiesis. This can lead to macrocytosis, where red blood cells are larger in size than average, or have an MCV greater than 100 fL. This also manifests clinically as reticulocytopenia, an abnormally low amount of reticulocytes.