Fig. 1.19 ). The dynamic relationship between stem cells and terminally differentiated parenchyma is nicely exemplified by the continuously dividing epithelium of the skin. Thus, stem cells at the basal layer of the epithelium progressively differentiate as they migrate to the upper layers of the epithelium before dying and being shed.
Under conditions of homeostasis, stem cells are characterized by two important properties:
Self-renewal, which permits stem cells to maintain their numbers. Self-renewal may follow asymmetric or symmetric division.
Asymmetric division refers to cell replication in which one daughter cell enters a differentiation pathway and gives rise to mature cells, whereas the other remains undifferentiated and retains its self-renewal capacity. By contrast, in symmetric division, both daughter cells retain self renewal capacity. Such divisions are seen early in embryogenesis (when stem cell populations are expanding) and under conditions of stress, such as in the bone marrow following chemotherapy.
Although there is a tendency in the scientific literature to partition stem cells into several different subsets, fundamentally there are only two varieties:
Embryonic stem cells (ES cells) are the most undifferentiated. They are present in the inner cell mass of the http://ebooksmedicine.net blastocyst, have virtually limitless cell renewal capacity, and can give rise to every cell in the body; they are thus said to be totipotent (
Fig. 1.20 ). ES cells can be maintained for extended periods without differentiating; thereafter, appropriate culture conditions allow them to form specialized cells of all three germ cell layers,
Fig. 1.19 Mechanismsregulatingcellpopulations.Cellnumberscanbealteredbyincreasedordecreasedratesofstemcellinput,celldeathresultingfromapoptosis,orchangesintheratesofproliferationordifferentiation.
(Modified from McCarthy NJ, et al: Apoptosis in the development of the immune system: growth factors, clonal selection and bcl-2, CancerMetastasisRev11:157, 1992.) including neurons, cardiac muscle, liver cells, and pancreatic islet cells.
• Tissue stem cells (also called adult stem cells) are found in intimate association with the differentiated cells of a given tissue. They are normally protected within specialized tissue microenvironments called stem cell niches. Such niches have been demonstrated in many organs, most notably the bone marrow, where hematopoietic stem cells congregate in a perivascular niche. Other niches for stem cells include the bulge region of hair follicles; the limbus of the cornea; the crypts of the gut; the canals of Hering in the liver; and the subventricular zone in the brain. Soluble factors and other cells within the niches keep the stem cells quiescent until there is a need for expansion and differentiation of the precursor pool (
Fig. 1.21
Adult stem cells have a limited repertoire of differentiated cells that they can generate. Thus, although adult stem cells can maintain tissues with high (e.g., skin and gastrointestinal tract) or low (e.g., endothelium) cell turnover, the adult stem cells in any given tissue can usually only produce cells that are normal constituents of that tissue.
Hematopoietic stem cells are the most extensively studied; they continuously replenish all the cellular elements of the blood as they are consumed. They can be isolated directly from bone marrow, as well as from the peripheral blood after administration of certain colony stimulating factors (CSF) that induce their release from bone marrow niches. Although rare, hematopoietic stem cells can be purified to virtual homogeneity based on cell surface markers. Clinically, these stem cells can be used to repopulate marrows depleted after chemotherapy (e.g., for leukemia), or to provide normal precursors to correct various blood cell defects (e.g., sickle cell disease; see Chapter 12).