Hematopoietic progenitor cells generally become committed to a particular pathway of differentiation long before they cease proliferating and terminally differentiate. The committed progenitors go through many rounds of cell division to amplify the ultimate number of cells of the given specialized type. In this way, a single stem-cell division can lead to the production of thousands of differentiated progeny, which explains why the number of stem cells is such a small fraction of the total population of hematopoietic cells. For the same reason, a high rate of blood cell production can be maintained even though the stem-cell division rate is low. The smaller the number of division cycles that the stem cells themselves have to undergo in the course of a lifetime, the lower the risk of generating stem-cell mutations, which would give rise to persistent mutant clones of cells in the body—a particular danger in the hematopoietic system where, as discussed in Chapter 20, a relatively small accumulation of mutations can be sufficient to cause cancer. A low rate of stem-cell division also slows the process of replicative cell senescence (discussed in Chapter 17).
Figure 22–31 A tentative scheme of hematopoiesis. the multipotent stem cell normally divides infrequently to generate either more multipotent stem cells, which are self-renewing, or committed progenitor cells, which are limited in the number of times that they can divide before differentiating to form mature blood cells. as they go through their divisions, the progenitors become progressively more specialized in the range of cell types that they can give rise to, as indicated by the branching of this cell-lineage diagram. in adult mammals, all of the cells shown develop mainly in the bone marrow—except for t lymphocytes, which as indicated develop in the thymus, and macrophages and osteoclasts, which develop from blood monocytes. Some dendritic cells may also derive from monocytes.
The stepwise nature of commitment means that the hematopoietic system can be viewed as a hierarchical family tree of cells. Multipotent stem cells give rise to committed progenitor cells, which are specified to give rise to only one or a few blood cell types. The committed progenitors divide rapidly, but only a limited number of times, before they terminally differentiate into cells that divide no further and die after several days or weeks. Figure 22–31 depicts the hematopoietic family tree. It should be noted, however, that variations are thought to occur: not all stem cells generate the identical patterns of progeny via precisely the same sequence of steps.
Like the stem cells of other tissues, hematopoietic stem cells depend on signals from their niche, in this case created by the specialized connective tissue of the bone marrow. (This is the site in adult humans; during development, and in nonhuman mammals such as the mouse, hematopoietic stem cells can also make their home in other tissues—notably liver and spleen.) When they lose contact with their niche, the hematopoietic stem cells tend to lose their stem-cell potential (Figure 22–32). Evidently the loss of potency is not absolute or instantaneous, however, since the stem cells can still survive journeys via the bloodstream to colonize other sites in the body.
While the stem cells depend on contact with bone marrow stromal cells for longterm maintenance, their committed progeny do not, or at least not to the same degree. These cells can thus be dispersed and cultured in a semisolid matrix of dilute agar or methylcellulose, and factors derived from other cells can be added artificially to the medium. The semisolid matrix inhibits migration, so that the progeny of each isolated precursor cell remain together as an easily distinguishable colony. A single committed neutrophil progenitor, for example, may give rise to a clone of thousands of neutrophils. Such culture systems have provided a way to assay for the factors that support hematopoiesis and hence to purify them and explore their actions. These substances are glycoproteins and are usually called colony-stimulating factors (CSFs). Some of these factors circulate in the blood and act as hormones, while others act in the bone marrow as secreted local mediators; still others take the form of membrane-bound signals that act through cell– cell contact.