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Hematopoiesis describes the production of cells that circulate in the bloodstream. Specifically, erythropoiesis is the process by which red blood cells (erythrocytes) are produced.
On average, the body produces an astounding 2.5 billion red cells/kg/day. Erythrocytes arise from a complex line of cells, and their rate of production is tightly regulated to ensure adequate but not excessive numbers of red blood cells are produced.
Sites of Erythropoiesis
The site of erythropoiesis changes throughout life. In the very early foetus, it occurs in the yolk sac. From 2 – 5 months’ gestation, it occurs in the liver and spleen before finally establishing in the bone marrow from about 5 months’ gestation.
In children, erythropoiesis can occur in the bone marrow of most bones. However, in adults, it only occurs in the bone marrow of the vertebrae, ribs, sternum, sacrum, pelvis, and proximal femur.
When erythropoiesis is inadequate in the bone marrow, this can trigger extramedullary hematopoiesis – i.e. hematopoiesis occurring outside the marrow. This is commonly seen in hemoglobinopathies, in particular thalassaemias and myelofibrosis.
Stages of Erythropoiesis
The production of all blood cells begins with the haemocytoblast, a multipotent hematopoietic stem cell. Haemocytoblasts have the greatest powers of self-renewal of any adult cell. They are found in the bone marrow and can be mobilized 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 erythroblasts), which are normally present in the bone marrow only.
Secondly, they lose some organelles and 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. These normally survive for around 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 indicates the release of incompletely developed cells. This can occur in pathologies such as thalassemia, severe anaemia, or hematological malignancy.
Regulation of Erythropoiesis
Erythropoiesis is driven mainly by the hormone erythropoietin (EPO), which is a glycoprotein cytokine.
EPO is secreted by the kidney. It is constantly secreted at a low level, sufficient for the normal regulation of erythropoiesis. However, if the erythrocyte level becomes inadequate, the blood becomes relatively hypoxic. When there is a reduced partial pressure of oxygen (pO2) in the kidney, this is detected by the renal interstitial peritubular cells.
In response, there is a surge in EPO production, which acts in the bone marrow to stimulate increased red blood cell production. This causes haemoglobin levels to increase, subsequently causing the pO2 to rise and therefore EPO levels to fall. The feedback loop is complete.