Stem cells: the generation and maintenance of cellular diversity

Abstract

Cell divisions during embryonic development give rise to new differentiated cell types or increase the total number of cells in the embryo. In contrast, the major role of cell division in adult life is to maintain the number of differentiated cells at a constant level: to replace cells that have died or been lost through injury.The rate at which new cells are produced in the adult is a measure of how rapidly the cell population is turning over and, on this basis, tissues can be divided into three broad categories (Leblond, 1963). In tissues with static cell populations, such as nerve and skeletal muscle, there is no cell division and most of the cells formed during development persist throughout adult life. In tissues containing conditional renewal populations, such as liver, there is generally little cell division, but in response to an appropriate stimulus most cells can divide to produce daughters of the same differentiated phenotype. Finally, tissues with perma-nently renewing populations, including blood, testis and stratified squamous epithelia, are characterized by rapid and continuous cell turnover in the adult: the terminally differentiated cells have a short lifespan and are replaced through proliferation of a distinct sub-population of cells, known as stem cells.The simplest definition of a stem cell is that it is any cell with a high capacity for self-renewal, extending throughout adult life. In addition, stem cells are usually considered to have the potential to produce differen-tiated progeny and, as such, a stem cell may have a less ‘mature’ or less ‘differentiated’ phenotype than its daughters (Lajtha, 1979). Using these criteria, most of the progenitor cell populations that arise during embry-onic development are not stem cells, since they do not self-renew; however, as we shall describe, they have a number of properties in common with the stem cells of adult organisms, including differentiation potential and capacity for asymmetric cell division.Three adult mammalian tissues in which stem cells have been extensively studied are the haemopoietic system, the epidermis and intestinal epithelium. In our review, we shall begin by describing these stem cell populations: the evidence that they exist; their identifi-cation, location and differentiated progeny. Three com-mon features that emerge are illustrated in Fig. 1A. First, stem cells have the capacity for unlimited self-renewal, in the context of the fifespan of the organism. Second, they have the potential for asymmetric div-isions, such that one daughter is itself a stem cell while the other is committed to undergo terminal differen-tiation. Third, the differentiation process is irreversible, since the daughters of a cell that is committed to terminal differentiation are never stem cells.In haemopoiesis and in intestinal epithelium, the stem cells are pluripotential, giving rise to more than one type of differentiated cell. In the epidermis, in contrast, there appears to be only a single pathway of terminal differentiation (Fig. IB). In all three tissues, (here is evidence that differentiation of stem cell progeny occurs via transit amplifying, or progenitor, populations that have a more limited capacity for self-renewal (Fig. 1B).We shall discuss what is known of the mechanisms that regulate these aspects of stem cell behaviour, drawing on the properties of analogous cells in a range of other tissues and organisms.The terminally differentiated cell types of blood, shown in Fig. 2, are all derived from pluripotential stem cells that are located in bone marrow. The first evidence for the existence of such a stem cell population came from experiments in which bone marrow cells from healthy mice were injected into mice that had received lethal doses of radiation (Ford et al. 1956; Till & McCulloch, 1961). The donor marrow was able to reconstitute all the differentiated blood cell types in the host and, when low numbers of cells were injected, colonies derived from single marrow cells (CFU-S) were found to contain both myeloid and erythroid cells (Wu et al. 1968). The use of chromosome markers induced by radiation or retroviral integration has confirmed that cells of myeloid and lymphoid lineages can all be derived from a single cell with high self-renewal ca-pacity (Abramson et al. 1977; Joyner et al. 1983; Williams et al. 1984; Dick et al. 1985; Lemischka et al. 1986).The haemopoietic stem cells do not give rise to terminally differentiated cells directly, but via prolifer-ating progenitor populations, as illustrated in Fig. 2. In this way, a relatively small number of stem cells (estimated as 0·4% of the total population of haemo-poietic cells; Lord & Testa, 1988) can give rise to a large number of terminally differentiated cells (Lajtha, 1979). Identification of the progenitors and investigation of the mechanisms regulating their profiferation and differen-tiation have been made possible by the development of cell culture systems that supp