I. Stem Cells and Their Derivatives

The adult human body, and all its differentiated cells, tissues, and organs, arise from a small group of cells contained within the early embryo at the blastocyst stage of its development. During in vivo embryonic development, these cells, constituting the inner cell mass (ICM), will divide and differentiate in concert with each other and with the whole of which they are a part, eventually producing the specialized and integrated tissues and organs of the body. But when embryos are grown [using in vitro fertilization (IVF)] in a laboratory setting, these ICM cells may be removed and isolated, and under appropriate conditions some will proliferate in vitro and become embryonic stem cell lines. These embryonic stem cells are capable of becoming many different types of differentiated cells if stimulated to do so in vitro [see endnote 2 for references]. However, it is not yet clear that the cells that survive the in vitro selection process to become embryonic stem cells have all of the same biological properties and potentials as the ICM cells of the blastocyst.7 In particular, it is not known for certain that human embryonic stem cells in vitro can give rise to all the different cell types of the adult body.iiAs noted in the Introduction to this report, stem cells are a diverse class of cells, which can now be isolated from a variety of embryonic, fetal, and adult tissues. Stem cells share two characteristic properties: (1) unlimited or prolonged self-renewal (that is, the capacity to maintain a pool of stem cells like themselves), and (2) potency for differentiation, the potential to produce more differentiated cell types—usually more than one and, in some cases, many.iii
When stem cells head down the pathway toward differentiation, they usually proceed by first giving rise to a more specialized kind of stem cell (sometimes called “precursor cells” or “progenitor cells”), which can in turn either proliferate through self-renewal or produce fully specialized or differentiated cells .

figure is an undifferentiated stem cell; in the central box are more “specialized” stem cells (or “precursor cells” or “progenitor cells”); at the bottom are various differentiated cells that are derived from the specialized stem cells. Dashed arrows indicate symmetrical (in the sense that both the daughter cells are stem cells) cell divisions that produce more stem cells (self-renewal). Solid arrows indicate asymmetric cell divisions that produce more differentiated daughter cells. (There may also be self-renewal with asymmetric division—not shown here—in which one daughter cell initiates a differentiation pathway while the other remains a stem cell.) Differentiation signals can be supplied by both soluble proteins and by specific, cell-surface binding sites. Some of the specialized stem cells inside the dashed box, for example, mesenchymal stem cells, can be isolated from tissues after birth and correspond to adult stem cells. Scientists are currently investigating whether, at least in some cases, the process can be reversed, that is, whether specialized cells may, on appropriate signals, dedifferentiate to become precursor or even fully undifferentiated stem cells.The terminology used to describe different stem cell types can be confusing. As used in this chapter, stem cells are self-renewing, cultured cells, grown and preserved in vitro, that are capable—upon exposure to appropriate signals—of differentiating themselves into (usually more than one) specialized cell types. Stem cells may be classified either according to their origins or according to their developmental potential. Stem cells may be obtained from various sources: from embryos, from fetal tissues, from umbilical cord blood, and from tissues of adults (or children). Thus, depending on their origin, stem cell preparations may be called adult stem cells,iv embryonic stem cells, embryonic germ cells, or fetal stem cells. Adult stem cells [see (4)] are cells derived from various tissues or organs in humans or animals that have the two characteristic properties of stem cells (self-renewal and potency for differentiation). Embryonic stem cells (ESCs) [see (2)] are derived from cells isolated from the inner cell mass of early embryos. Embryonic germ cells (EGCs) [see (1)] are stem cells derived from the primordial germ cells of a fetus. Fetal stem cells (not further discussed in this chapter, but included for the sake of completeness) are derived from the developing tissues and organs of fetuses; because they come (unlike EGCs) from already differentiated tissues, they are (like adult stem cells) “non-embryonic,” and may be expected to behave as such.Depending on their developmental potential, cells may be called pluripotent, multipotent, or unipotent. Cells that can produce all the cell types of the developing body, such as the ICM cells of the blastocyst, are said to be pluripotent. The somewhat more specialized stem cells, of the sort found in the developed organs or tissues of the body, are said to be multipotent if they produce more than one differentiated tissue cell type, and unipotent if they produce only one differentiated tissue cell type. We introduce in this chapter an additional term: stem cell preparation. A stem cell preparation is a population of stem cells, prepared, grown, and preserved under certain conditions. Because different laboratories (or even the same one) can have different preparations of the same type of stem cell, it is important to recognize the potential differences between particular preparations of embryonic stem cells.v It will sometimes be important to call attention to this fact, by speaking of a “preparation of ES cells” (or a preparation of adult stem cells) rather than of “ES cells,” pure and simple. We will use the term “stem cell preparations” when we are speaking of a diverse group of stem cell cultures, when we are speaking of stem cell cultures that contain an admixture of other types of cells, or when the developmental homogeneity of the stem cells in the population has not been defined.Adult and embryonic stem cell populations have also been called “stem cell lines.” In the past, the term “cell line” denoted a cell population (usually of cancer cells containing abnormal chromosome numbers or structure, or both) that could grow “indefinitely” in vitro. Embryonic and some adult stem cell preparations are capable of prolonged growth beyond 50 population doublings in vitro while retaining their characteristic stem cell properties and initially with no change in the chromosome numbers and structure. It is not yet known whether any preparation of human ES cells (generally believed to be much longer-lived than adult stem cells) will continue to grow “indefinitely,” without undergoing genetic changes.Under the influence of various cell-differentiation signals, embryonic stem cells differentiate into numerous distinct types of more specialized cells. Some of these are specialized stem cells that can also self-renew, while retaining their ability also to differentiate into multiple cell types. Recent research has led to the isolation of an increasing number of adult (non-embryonic) stem cells (dashed box area of Figure 1) from such tissues as bone marrow (for example, hematopoietic and mesenchymal stem cells), brain (for example, neural stem cells) and other tissues [see (4)]. Although these stem cell preparations differ from one another in their future fates, they tend to be grouped together (especially in the public policy debates) under the name “adult stem cells,” even though they may have been obtained from children or even from umbilical cord blood obtained at the time of childbirth.Subsequent exposure to additional differentiation signals can cause these specialized stem cells to differentiate further, so that they finally give rise to the variety of differentiated cells that make up the adult body (labeled A-D in Figure 1). At each stage of the differentiation process, specific sets of genes are expressed (or “turned on”) and other sets are repressed (or “turned off”), to produce the specific proteins that give each cell its distinctive properties. At each stage along the way, proteins called transcription factors play key roles in determining which sets of genes are expressed and repressed, and therefore what sort of a cell the newly differentiated cell will become.