The bone marrow is the site of generation of circulating blood cells, including red blood cells, granulocytes, and monocytes, and the site of most steps of B-cell maturation. The generation of all blood cells, called hematopoiesis (Fig. 1), occurs initially during fetal development in blood islands of the yolk sac and the para-aortic mesenchyme, shifts to the liver between the third and fourth months of gestation, and finally shifts to the bone marrow. At birth, hematopoiesis takes place in the bones throughout the skeleton, but it becomes increasingly restricted to the marrow of the flat bones, so that by puberty, hematopoiesis occurs mostly in the sternum, vertebrae, iliac bones, and ribs. The red marrow that is found in these bones consists of a spongelike reticular framework located between long, bony trabeculae. The spaces in this framework contain a network of blood-filled sinusoids lined by endothelial cells attached to a discontinuous basement membrane. Outside the sinusoids are clusters of the precursors of blood cells in various stages of development, as well as fat cells. The blood cell precursors mature and then migrate through the sinusoidal basement membrane and between endothelial cells to enter the vascular circulation. When the bone marrow is compromised or there is an exceptional demand for production of new blood cells, the liver and spleen often become sites of extramedullary hematopoiesis.
Fig1. Hematopoiesis. The development of the major lineages of blood cells is depicted in this hematopoietic tree. The principal cytokines that drive the maturation of different lineages are described in Table 2.6. The development of lymphocytes is described later in this chapter and in Chapter 8. CFU, Colony-forming unit; CFU-Mc, CFU mast cell; CFU-b, CFU B cell; CFU-eo, CFU eosinophil; CFU-G, CFU granulocytes; CFU-M, CFU macrophages; DC, dendritic cell; ILCs, innate lymphoid cells; NK, natural killer.
Red blood cells, granulocytes, monocytes, DCs, mast cells, platelets, B and T lymphocytes, and ILCs all originate from a common HSC in the bone marrow (see Fig. 1). HSCs are multipotent, meaning that a single HSC can generate all different types of mature blood cells. HSCs are also self-renewing because each time they divide, one daughter cell maintains the properties of a stem cell and the other can differentiate along a particular lineage (called asymmetric division). HSCs can be identified by the presence of surface markers, including the proteins CD34 and c-KIT, and the absence of lineage-specific markers that are expressed in mature cells. HSCs are maintained within specialized anatomic niches in the bone marrow. In these locations, nonhematopoietic stromal cells provide contact dependent signals and growth factors required for continuous cycling and differentiation of the HSCs. The common myeloid lymphoid progenitor gives rise to some myeloid cells and to committed precursors of T-cell, B-cell, and NK/ILC lineages. The common myeloid-megakaryocyte-erythroid progenitors give rise to committed precursors of the erythroid, megakaryocytic, granulocytic, and monocytic lineages, which give rise, respectively, to mature red blood cells, platelets, granulocytes (neutrophils, eosinophils, basophils), and monocytes. As dis cussed earlier, most DCs arise from a precursor that also gives rise to monocytes. Immature mast cell progenitors arise from a common granulocyte/monocyte precursor, leave the bone mar row, and mature into mast cells in peripheral tissues.
The proliferation and maturation of precursor cells in the bone marrow are stimulated by cytokines. Many of these cytokines are called colony-stimulating factors because they were originally assayed by their ability to stimulate the growth and development of various leukocytic or erythroid colonies from marrow cells. Hematopoietic cytokines are produced by stromal cells and macro phages in the bone marrow, thus providing the local environment for hematopoiesis. They are also produced by antigen-stimulated T lymphocytes and cytokine-activated or microbe-activated macro phages, providing a mechanism for increasing leukocyte production when needed for immune and inflammatory reactions and for replenishing leukocytes that may be consumed during these reactions. The names and properties of the major hematopoietic cytokines for immune cells are listed in Table 2.
Table1. Hematopoietic Cytokines for Immune Cells
In addition to self-renewing stem cells and their differentiating progeny, the marrow contains numerous long-lived antibody-secreting plasma cells. These cells are generated in secondary lymphoid organs as a consequence of stimulation of B cells by antigens and helper T cells, and then migrate to the bone marrow. In addition, some long-lived memory T lymphocytes migrate to and reside in the bone marrow.
