The default behavior of hematopoietic cells in the absence of CSFs is death by apoptosis (discussed in Chapter 18), and the control of cell survival plays a central part in regulating the numbers of blood cells. The amount of apoptosis in the vertebrate hematopoietic system is enormous: billions of neutrophils die in this way each day in an adult human, for example. In fact, most neutrophils produced in the bone marrow die there without ever functioning. This futile cycle of production and destruction presumably serves to maintain a reserve supply of cells that can be promptly mobilized to fight infection whenever it flares up, or phagocytosed and digested for recycling when all is quiet. Compared with the life of the organism, the lives of cells are cheap.
Too little cell death can be as dangerous to the health of a multicellular organism as too much proliferation. As noted in Chapter 18, mutations that inhibit cell death by causing excessive production of the intracellular apoptosis inhibitor
Figure 22–34 Some of the parameters through which the production of blood cells of a specific type might be regulated. Studies in culture suggest that various colony-stimulating factors (CSFs) can affect all of these aspects of hematopoiesis.
Bcl2 promote the development of cancer in B lymphocytes. Indeed, the capacity for unlimited self-renewal is a dangerous property for any cell to possess. Many cases of leukemia arise through mutations that confer this capacity on committed hematopoietic precursor cells that would normally be fated to differentiate and die after a limited number of division cycles.
The many types of blood cells, including erythrocytes, lymphocytes, granulocytes, and macrophages, all derive from a common multipotent stem cell. In the adult, hematopoietic stem cells are found mainly in bone marrow, and they depend on signals from the marrow stromal (connective-tissue) cells to maintain their stem-cell character. The stem cells are few and far between, and they normally divide infrequently to produce more stem cells (self-renewal) and various committed progenitor cells (transit amplifying cells), each able to give rise to only one or a few types of blood cells. The committed progenitor cells divide extensively under the influence of various protein signal molecules (colony-stimulating factors, or CSFs) and then terminally differentiate into mature blood cells, which usually die after several days or weeks.
Studies of hematopoiesis have been greatly aided by in vitro assays in which stem cells or committed progenitor cells form clonal colonies when cultured in a semisolid matrix. The progeny of stem cells seem to make their choices between alternative developmental pathways in a partly random manner. Cell death by apoptosis, controlled by the availability of CSFs, also plays a central part in regulating the numbers of mature differentiated blood cells.
As we have seen, many of the tissues of the body are not only self-renewing but also self-repairing, and this is largely thanks to stem cells and the feedback controls that regulate their behavior and maintain homeostasis. There are, however, limits to what these natural repair mechanisms can achieve. In most parts of the human brain, for example, nerve cells that die, as in Alzheimer’s disease, are not replaced. Likewise, when heart muscle dies for lack of oxygen, as in a heart attack, it is replaced by scar tissue rather than new heart muscle.
Some animals do far better than humans and can regenerate entire organs, such as whole limbs, after amputation. Among the invertebrates, there are some species that can even regenerate all the tissues of the body from a single somatic cell. These phenomena encourage the hope that human cells might be coaxed by artificial measures into similar feats of repair and regeneration, so as to replace the skeletal muscle fibers that degenerate in victims of muscular dystrophy, the nerve cells that die in patients with Parkinson’s disease, the insulin-secreting cells that are lacking in type 1 diabetics, the heart muscle cells that die in a heart attack, and so on. As we learn more about the basic cell biology, these goals, once only a dream, are beginning to seem attainable.