Monocytes are produced in the bone marrow from a GMP stem cell that can mature into a monocyte or another of the three granulocytic cell lines. In addition, GMP gives rise to dendritic cells. The proliferation and differentiation of CMP into committed GMP is controlled by IL-3. Further progression of monocyte progenitor (MoP) cell lineage depends on the continued presence of PU.1 and Egr-1 transcription factors and is stimulated by IL-3 and GM-CSF. The GMCSF also controls further differentiation into mature cells, which are then released into circulation. The transformation of MoPs to monocytes takes about 55 hours, and the monocytes remain in the circulation for only about 16 hours before emigrating to the tissues where they differentiate under influence of both GM-CSF and M-CSF into tissue macrophages. Their subsequent life span is not yet fully understood.
Development of Lymphocytes (Lymphopoiesis)
Development and lineage commitment of CLP cells depend on the expression of variety of transcription factors.
Although lymphocytes continuously proliferate in the peripheral lymphatic organs, the bone marrow remains the primary site of lymphopoiesis in humans. Members of the Ikaros family of transcription factors play major roles in the differentiation of pluripotent HSCs toward common lymphoid progenitor (CLP) cells. Progeny of the CLP cells that express GATA-3 transcription factor are destined to become T lymphocytes. These cells that express GATA-3 leave the bone marrow as pre–T lymphocytes and travel to the thymus, where they complete their differentiation and thymic cell education (see Chapter 14, Lymphatic System). They then enter the circulation as long-lived, small T lymphocytes. Another transcription factor, Pax5, activates B-cell–specific genes in CLP cells destined to become B lymphocytes. In mammals, these cells originate in bursa-equivalent organs such as the bone marrow, gut-associated lymphatic tissue, and spleen. Although a number of transcription factors have been identified in the development of lymphoid cell lineages, little is known about factors that may influence development and lineage commitment of NK cells. NK cells most likely differentiate under the influence of IL-2 and IL-15 into immature pre–NK cells, and, after acquisition of NK–cell effector functions (ability to secrete interferon and cytotoxicity), become mature NK cells. The bone marrow is the main NK cell–producing organ. However, recent studies suggest that lymph nodes or fetal thymus may also contain NK-progenitor cells. Lymphocytes constitute as much as 30% of all nucleated cells in the bone marrow. The production and differentiation of lymphocytes are discussed in more detail in Chapter 14, Lymphatic System.
Red bone marrow lies entirely within the spaces of bone, medullary cavity of young long bones, and spaces of spongy bone.
Bone marrow consists of blood vessels, specialized units of blood vessels called sinusoids, and a spongelike network of hemopoietic cells (Fig. 10.22). The bone marrow sinusoids provide the barrier between the hemopoietic compartment and the peripheral circulation. In sections, the cells in hemopoietic compartment appear to lie in “cords” between sinusoids or between sinusoids and bone.
The sinusoid of red bone marrow is a unique vascular unit. It occupies the position normally occupied by a capillary; that is, it is interposed between arteries and veins. It is believed to be derived from vessels that have just nourished the cortical bone tissue. The sinusoids arise from these vessels at the corticomedullary junction. The sinusoid wall consists of an endothelial lining, a basal lamina, and an incomplete covering of adventitial cells. The endothelium is a simple squamous epithelium.