11.2 Production of Formed Elements

Sites of Hematopoiesis

Prior to birth, hematopoiesis occurs in a number of tissues, beginning with the yolk sac of the developing embryo, and continuing in the fetal liver, spleen, lymphatic tissue, and eventually the red bone marrow. Following birth, most hematopoiesis occurs in the red marrow, a connective tissue within the spaces of spongy (cancellous) bone tissue. In children, hematopoiesis can occur in the medullary cavity of long bones; in adults, the process is largely restricted to the cranial and pelvic bones, the vertebrae, the sternum, and the proximal epiphyses of the femur and humerus.

Throughout adulthood, the liver and spleen maintain their ability to generate formed elements. This process is referred to as extramedullary hematopoiesis (meaning hematopoiesis outside the medullary cavity of adult bones). When a disease such as bone cancer destroys the bone marrow, causing hematopoiesis to fail, extramedullary hematopoiesis may be initiated.

Differentiation of Formed Elements from Stem Cells

All formed elements arise from stem cells of the red bone marrow. Recall that stem cells undergo mitosis plus cytokinesis (cellular division) to give rise to new daughter cells. One of these daughter cells remains a stem cell and the other differentiates into one of any number of diverse cell types. Stem cells may be viewed as occupying a hierarchal system, with some loss of the ability to diversify at each step. The totipotent stem cell is the zygote, or fertilized egg. The totipotent (“toti-” meaning “all”) stem cell gives rise to all cells of the human body. The next level is the pluripotent stem cell, which gives rise to multiple types of cells of the body and some of the supporting fetal membranes. Beneath this level, the mesenchymal cell is a stem cell that develops only into types of connective tissue, including fibrous connective tissue, bone, cartilage, and blood, but not epithelium, muscle, and nervous tissue. One step lower on the hierarchy of stem cells is the hematopoietic stem cell, or hemocytoblast. All of the formed elements of blood originate from this specific type of cell.

Hematopoiesis begins when the hematopoietic stem cell is exposed to appropriate chemical stimuli collectively called hematopoietic growth factors, which prompt it to divide and differentiate. One daughter cell remains a hematopoietic stem cell, allowing hematopoiesis to continue. The other daughter cell becomes either of two types of more specialized stem cells (Figure 11.2.1):

• Lymphoid stem cells give rise to a class of leukocytes known as lymphocytes, which include the various T cells, B cells, and natural killer (NK) cells, all of which function in immunity. However, hematopoiesis of lymphocytes progresses somewhat differently from the process for the other formed elements. In brief, lymphoid stem cells quickly migrate from the bone marrow to lymphatic tissues, including the lymph nodes, spleen, and thymus, where their production and differentiation continues. B cells are so named since they mature in the bone marrow, while T cells mature in the thymus.
• Myeloid stem cells give rise to all the other formed elements, including the erythrocytes; megakaryocytes that produce platelets; and a myeloblast lineage that gives rise to monocytes and three forms of granular leukocytes: neutrophils, eosinophils, and basophils.

Lymphoid and myeloid stem cells do not immediately divide and differentiate into mature formed elements. As you can see in Figure 1, there are several intermediate stages of precursor cells, many of which can be recognized by their names, which have the suffix -blast. For instance, megakaryoblasts are the precursors of megakaryocytes, and proerythroblasts become reticulocytes, which eject their nucleus and most other organelles before maturing into erythrocytes.

Hematopoietic Growth Factors

Development from stem cells to precursor cells to mature cells is initiated by hematopoietic growth factors. These include the following:

• Erythropoietin (EPO) is a glycoprotein hormone secreted by the interstitial fibroblast cells of the kidneys in response to hypoxia (e.g., low oxygen levels). It prompts the production of erythrocytes by bone marrow. When kidneys sense hypoxia at the tissue level due to decreased RBC count, decreased hemoglobin, or decreased availability of oxygen, they increase their release of EPO. Some athletes use synthetic EPO as a performance-enhancing drug (called blood doping) because increased EPO leads to an increased amount of RBCs, which increases oxygen delivery to tissues throughout the body; and potentially improving performance. EPO is a banned substance in most organized sports, but it is also used medically in the treatment of certain anemia, specifically those triggered by certain types of cancer, and other disorders in which increased erythrocyte counts and oxygen levels are desirable.
• Thrombopoietin, another glycoprotein hormone, is produced by the liver and kidneys. It triggers the development of megakaryocytes into platelets.
• Cytokines are glycoproteins secreted by a wide variety of cells, including red bone marrow, leukocytes, macrophages, fibroblasts, and endothelial cells. They act locally as autocrine or paracrine factors, stimulating the proliferation of progenitor cells and helping to stimulate both nonspecific and specific resistance to disease. There are two major subtypes of cytokines known as colony-stimulating factors and interleukins.
  • Colony-stimulating factors (CSFs) are glycoproteins that act locally as autocrine or paracrine factors. Some trigger the differentiation of myeloblasts into granular leukocytes, namely, neutrophils, eosinophils, and basophils. These are referred to as granulocyte CSF or G-CSFs. A different CSF induces the production of monocytes, called monocyte CSF or M-CSFs. Both granulocytes and monocytes are stimulated by GM-CSF; granulocytes, monocytes, platelets, and erythrocytes are stimulated by multi-CSF. Synthetic forms of these hormones are often administered to patients with various forms of cancer who are receiving chemotherapy to revive their WBC counts.
  • Interleukins are another class of cytokine signaling molecules important in hemopoiesis. They were initially thought to be secreted uniquely by leukocytes and to communicate only with other leukocytes, and were named accordingly, but are now known to be produced by a variety of cells including bone marrow and endothelium. Researchers now suspect that interleukins may play other roles in body functioning, including differentiation and maturation of cells, producing immunity, and inflammation. To date, close to 40 interleukins have been identified, and more are likely to be discovered. They are generally numbered IL-1, IL-2, IL-3, etc.

Bone Marrow Sampling and Transplants

For certain medical conditions, a health care provider could order a bone marrow biopsy, a diagnostic test of a sample of red bone marrow, or a bone marrow transplant, a treatment in which a donor’s healthy bone marrow—and its stem cells—replaces the faulty or damaged bone marrow of a patient. These tests and procedures are often used to assist in the diagnosis and treatment of various severe forms of anemia, such as thalassemia major and sickle cell anemia, as well as some types of cancer, specifically leukemia.

In the past, when a bone marrow sample or transplant was necessary, the procedure would have required inserting a large-bore needle into the region near the iliac crest of the pelvic bones. This location was preferred, since its location close to the body surface makes it more accessible, and it is relatively isolated from most vital organs. Unfortunately, the procedure is quite painful.

Now, direct sampling of bone marrow can often be avoided. In many cases, stem cells can be isolated in just a few hours from a sample of a patient’s blood. The isolated stem cells are then grown in culture using the appropriate hematopoietic growth factors, and analyzed or sometimes frozen for later use.

For an individual requiring a transplant, a matching donor is essential to prevent the immune system from destroying the donor cells—a phenomenon known as tissue rejection. To treat patients with bone marrow transplants, it is first necessary to destroy the patient’s own diseased marrow through radiation and/or chemotherapy. Donor bone marrow stem cells are then intravenously infused. From the bloodstream, they establish themselves in the recipient’s bone marrow.