Blood cells are constantly formed through a process called hematopoiesis (also called hemopoiesis). The hematopoietic stem cells—those that give rise to blood cells—originate in the yolk sac of the human embryo and then migrate to the liver. Hematopoiesis thus occurs in the liver of the fetus. The stem
Heart and Circulation cells then migrate to the bone marrow, and shortly after birth the liver ceases to be a source of blood cell production.
The term erythropoiesis refers to the formation of erythrocytes, and leukopoiesis to the formation of leukocytes. These processes occur in two classes of tissues after birth, myeloid and lymphoid. Myeloid tissue is the red bone marrow of the long bones, ribs, sternum, pelvis, bodies of the vertebrae, and portions of the skull. Lymphoid tissue includes the lymph nodes, tonsils, spleen, and thymus. The bone marrow produces all of the different types of blood cells; the lymphoid tissue produces lymphocytes derived from cells that originated in the bone marrow.
Hematopoiesis begins the same way in both myeloid and lymphoid tissue. A population of undifferentiated (unspecial-ized) cells gradually differentiate (specialize) to become stem cells, which give rise to the blood cells. At each step along the way the stem cells can duplicate themselves by mitosis, thus ensuring that the parent population will never become depleted. As the cells become differentiated, they develop membrane receptors for chemical signals that cause further development along particular lines. The earliest cells that can be distinguished under a microscope are the erythroblasts (which become erythro-cytes), myeloblasts (which become granular leukocytes), lym-phoblasts (which form lymphocytes), and monoblasts (which form monocytes).
Erythropoiesis is an extremely active process. It is estimated that about 2.5 million erythrocytes are produced every second in order to replace those that are continuously destroyed by the spleen and liver. The life span of an erythrocyte is approximately 120 days. Agranular leukocytes remain functional for 100 to 300 days under normal conditions. Granular leukocytes, by contrast, have an extremely short life span of 12 hours to 3 days.
The production of different subtypes of leukocytes is stimulated by chemicals called cytokines. These are autocrine regulators secreted by various cells of the immune system. The particular cytokines involved in leukopoiesis are discussed below. The production of red blood cells is stimulated by the hormone erythropoietin, which is secreted by the kidneys. The gene for erythropoietin has been commercially cloned, so that this hormone is now available for the treatment of the anemia that results from kidney disease in patients undergoing dialysis.
Scientists have identified a specific cytokine that stimulates proliferation of megakaryocytes and their maturation into platelets. By analogy with erythropoietin, they named this regulatory molecule thrombopoietin. The gene that codes for thrombopoietin also has been cloned, so that recombinant thrombopoietin is now available for medical research and applications. In clinical trials, throm-bopoietin has been used to treat the thrombocytopenia (low platelet count) that occurs as a result of bone marrow depletion in patients undergoing chemotherapy for cancer.
A variety of cytokines stimulate different stages of leukocyte development. The cytokines known as multipotent growth factor-1, interleukin-1, and interleukin-3 have general effects, stimulating the development of different types of white blood cells. Granulo-cyte colony-stimulating factor (G-CSF) acts in a highly specific manner to stimulate the development of neutrophils, whereas granulocyte-monocyte colony-stimulating factor (GM-CSF) stimulates the development of monocytes and eosinophils. The genes for the cytokines G-CSF and GM-CSF have been cloned, making these cytokines available for medical applications.
Approximately 10,000 bone marrow transplants are performed worldwide each year. This procedure generally involves the aspiration of marrow from the iliac crest and separation of the hematopoietic stem cells, which constitute only about 1% of the nucleated cells in the marrow. Stem cells have also been isolated from peripheral blood when the donor is first injected with G-CSF and GM-CSF, which stimulate the marrow to release more stem cells. Another recent technology involves the storage, or "banking," of hematopoietic stem cells obtained from the placenta or umbilical cord blood of a neonate. These cells may then be used later in life if the person needs them for transplantation.
The primary regulator of erythropoiesis is erythropoietin, secreted by the kidneys whenever blood oxygen levels are decreased. One of the possible causes of decreased blood oxygen levels is a decreased red blood cell count. Because of erythro-poietin stimulation, the daily production of new red blood cells compensates for the daily destruction of old red blood cells, preventing a decrease in the blood oxygen content. An increased secretion of erythropoietin and production of new red blood cells occurs when a person is at a high altitude or has lung disease, which are conditions that reduce the oxygen content of the blood.
Erythropoietin acts by binding to membrane receptors on cells that will become erythroblasts (fig. 13.4). The erythropoietin-stimulated cells undergo cell division and differentiation, leading to the production of erythroblasts. These are transformed into normoblasts, which lose their nuclei to become reticulo-cytes. The reticulocytes then change into fully mature erythro-cytes. This process takes 3 days; the reticulocyte normally stays in the bone marrow for the first 2 days and then circulates in the blood on the third day. At the end of the erythro-cyte life span of 120 days, the old red blood cells are removed by phagocytic cells of the spleen, liver, and bone marrow. Most of the iron contained in the hemoglobin molecules of the destroyed red blood cells is recycled back to the myeloid tissue to be used in the production of hemoglobin for new red blood cells (see chapter 18, fig. 18.23). The production of red blood cells and synthesis of hemoglobin depends on the supply of iron, along with that of vitamin Bj2 and folic acid.
372 Chapter Thirteen
Nucleus expelled j
In bone marrow (myeloid tissue)
■ Figure 13.4 The stages of erythropoiesis. The proliferation and differentiation of cells that will become mature erythrocytes (red blood cells) occurs in the bone marrow and is stimulated by the hormone erythropoietin, secreted by the kidneys.
Because of the recycling of iron, dietary requirements for iron are usually quite small. Males (and women after menopause) have a dietary iron requirement of only about 10 mg/day. Women with average menstrual blood loss need 15 mg/day, and pregnant women need 30 mg/day. Because of these relatively small dietary requirements, iron-deficiency anemia in adults is usually not due to a dietary deficiency but rather to blood loss, which reduces the amount of iron that can be recycled.
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