Outline

22.1 The Birth of Cells

22.2 Cell-Type Specification in Yeast

22.3 Specification and Differentiation of Muscle

22.4 Regulation of Asymmetric Cell Division

22.5 Cell Death and Its Regulation

► FIGURE 22-1 Overview of the birth, lineage, and death of cells. Following growth, cells are "born" as the result of symmetric or asymmetric cell division. (a) The two daughter cells resulting from symmetric division are essentially identical to each other and to the parental cell. Such daughter cells subsequently can have different fates if they are exposed to different signals. The two daughter cells resulting from asymmetric division differ from birth and consequently have different fates. Asymmetric division commonly is preceded by the localization of regulatory molecules (green) in one part of the parent cell. (b) A series of symmetric and/or asymmetric cell divisions, called a cell lineage, gives birth to each of the specialized cell types found in a multicellular organism. The pattern of cell lineage can be under tight genetic control. Programmed cell death occurs during normal development (e.g., in the webbing that initially develops when fingers grow) and also in response to infection or poison. A series of specific programmed events, called apoptosis, is activated is these situations.

coordinately activate, or repress, batteries of genes that direct the differentiation process. For instance, a few key regulatory transcription factors create the different mating types of budding yeast and coordinate the numerous genes necessary to turn a precursor cell into a muscle cell, two examples that we discuss in this chapter.

Typically we think of cell fates in terms of the differentiated cell types that are formed. A quite different cell fate, programmed cell death, also is absolutely crucial in the formation and maintenance of many tissues. A precise genetic regulatory system, with checks and balances, controls cell death just as other genetic programs control cell differentiation. In this chapter, then, we consider the life cycle of cells— their birth, their patterns of division (lineage), and their death. These aspects of cell biology converge with developmental biology and are among the most important processes regulated by various signaling pathways discussed in earlier chapters.

The Birth of Cells

Many descriptions of cell division imply that the parental cell gives rise to two daughter cells that look and behave exactly like the parental cell, that is, cell division is symmetric, and the progeny do not change their properties. But if this were always the case, none of the hundreds of differentiated cell types would ever be formed. Differences among cells can arise when two initially identical daughter cells diverge by receiving distinct developmental or environmental signals. Alternatively, the two daughter cells may differ from "birth," with each inheriting different parts of the parental cell (see Figure 22-1). Daughter cells produced by such asymmetric cell division may differ in size, shape, and/or composition, or their genes may be in different states of activity or potential activity. The differences in these internal signals confer different fates on the two cells.

Here we discuss some general features of how different cell types are generated, culminating with the best-understood complex cell lineage, that of the nematode Caenorhabditis elegans. In later sections, we focus on examples of the molecular mechanisms that determine particular cell types in yeast, Drosophila, and mammals.

Stem Cells Give Rise to Stem Cells and to Differentiating Cells

Stem cells, which give rise to the specialized cells composing the tissues of the body, exhibit several patterns of cell division. A stem cell may divide symmetrically to yield two daughter stem cells identical to itself (Figure 22-2a). Alternatively, a stem cell may divide asymmetrically to generate a copy of itself and a derivative stem cell that has more-restricted capabilities, such as dividing for a limited period of time or giving rise to fewer types of progeny compared with the parental stem cell (Figure 22-2b). A pluripotent (or multipotent) stem cell has the capability of generating a number of different cell types, but not all. For instance, a pluripotent blood stem cell will form more of itself plus multiple types of blood cells, but never a skin cell. In contrast, a unipotent stem cell divides to form a copy of itself plus a cell that can form only one cell type. In many cases, asymmetric division of a stem cell generates a progenitor cell, which embarks on a path of differentiation, or even a terminally differentiating cell (Figure 22-2c, d).

▲ FIGURE 22-2 Patterns of stem-cell division. (a) Division of a stem cell produces two cells, one of which is a stem cell like the mother cell. In this way the population of stem cells is maintained. (b) The other daughter cell—a stem cell of more-restricted potential—starts on a pathway toward producing more differentiated cells. When it divides, one of the daughters will be the same sort of restricted-potential stem cell as the mother and the other will be a progenitor cell for a certain type of differentiated cell. Progenitor cells can divide to reproduce themselves and, in response to appropriate signals, can differentiate into a terminally differentiated, nondividing cell.

The two critical properties of stem cells that together distinguish them from all other cells are the ability to reproduce themselves indefinitely, often called self-renewal, and the ability to divide asymmetrically to form one daughter stem cell identical to itself and one daughter cell that is different and usually of more restricted potential. In this way, mitotic division of stem cells preserves a population of undifferentiated cells while steadily producing a stream of differentiating cells. Although some types of precursor cells can divide symmetrically to form more of themselves, they do so only for limited periods of time. Moreover, in contrast to stem cells, if a precursor cell divides asymmetrically, it generates two distinct daughter cells, neither of which is identical to the parental precursor cell.

The fertilized egg, or zygote, is the ultimate totipotent cell because it has the capability to generate all the cell types of the body. Although not technically a stem cell because it is not self-renewing, the zygote does give rise to cells with stem-cell properties. For example, the early mouse embryo passes through an eight-cell stage in which each cell can give rise to any cell type of the embryo. If the eight cells are experimentally separated and individually implanted into a suitable foster mother, each can form a whole mouse with no parts missing. This experiment shows that the eight cells are all able to form every tissue; that is, they are totipotent. Thus the subdivision of body parts and tissue fates among the early embryonic cells has not irreversibly occurred at the eight-cell stage. At the 16-cell stage, this is no longer true; some of the cells are committed to particular differentiation paths.

Quite different specialized cell types can arise from a common precursor cell. A hematopoietic stem cell can give rise to all the multifarious types of blood cell. However, a whole series of cell divisions is not required; a single division of a pluripotent precursor cell can yield distinct progeny. For instance, lineage studies in which cells are marked by stable infection with a detectable retrovirus have shown that neurons and glial cells can arise from a single division of a particular precursor cell. These cell types are quite different: neurons propagating and transmitting electrical signals and glial cells providing electrical insulation and support. The precursor that generates neurons and glial cells is not a stem cell, since it is incapable of self-renewal; presumably the neuron-glial cell precursor arises from a stem cell further back in the lineage. Recent observations have raised the interesting possibility that stem cells for one tissue may be induced under certain conditions to act as stem cells for a rather different tissue. As we discuss below, postnatal animals contain stem cells for many tissues including the blood, intestine, skin, ovaries and testes, muscle, and liver. Even some parts of the adult brain, where little cell division normally occurs, has a population of stem cells. In muscle and liver, stem cells are most important in healing, as relatively little cell division occurs in the adult tissues otherwise.

Cultured Embryonic Stem Cells Can Differentiate into Various Cell Types

Embryonic stem (ES) cells can be isolated from early mammalian embryos and grown in culture (Figure 22-3a). Cultured ES cells can differentiate into a wide range of cell types, either in vitro or after reinsertion into a host embryo. When grown in suspension culture, human ES cells first differentiate into multicellular aggregates, called embryoid bodies, that resemble early embryos in the variety of tissues they form. When these are subsequently transferred to a solid medium, they grow into confluent cell sheets containing a variety of differentiated cell types including neural cells and pigmented and nonpigmented epithelial cells (Figure 22-3b). Under other conditions, ES cells have been induced to differentiate into precursors for various types of blood cells.

► EXPERIMENTAL FIGURE 22-3

Embryonic stem (ES) cells can be maintained in culture and form differentiated cell types. (a) Human blastocysts are grown from cleavage-stage embryos produced by In vitro fertilization. The inner cell mass is separated from the surrounding extra-embryonic tissues and plated onto a layer of fibroblast cells that help to nourish the embryonic cells. Individual cells are replated and form colonies of ES cells, which can be maintained for many generations and can be stored frozen. (b) In suspension culture, human ES cells differentiate into multicellular aggregates (embryoid bodies) (top). After embryoid bodies are transferred to a gelatinized solid medium, they differentiate further into confluent cell sheets containing a variety of differentiated cell types including neural cells (middle), and pigmented and nonpigmented epithelial cells (bottom). [Parts (a) and (b) adapted from J. S. Odorico et al., 2001, Stem Cells 19:193-204.]

The possibility of using stem cells therapeutically to restore or replace damaged tissue is fueling much research on how to recognize and culture these remarkable cells from embryos and from various tissues in postnatal (adult) animals. For example, if neurons that produce the neurotransmitter dopamine could be generated from stem cells grown in culture, it might be possible to treat people with Parkinson's disease who have lost such neurons. For such an approach to succeed, a way must be found to direct a population of embryonic or other stem cells to form the right type of dopamine-producing neurons, and rejection by the immune system nust be prevented. In one ongoing study in which embryonic neurons were transplanted into more than 300 Parkinson's patients, some of the inserted cells have survived for more than 12 years and have provided significant clinical improvement. However, the fetal tissue used in this study is scarce and its use is controversial. Stem cells grown from very early embryos are another option for treating Parkinson's disease and perhaps other neurodegenerative conditions such as Alzheimer's disease. Similar possibilities exist for generating blood, pancreas, and other cell types. Many important questions must be answered before the feasibility of using stem cells for such purposes can be assessed adequately. I

Apart from their possible benefit in treating disease, ES cells have already proven invaluable for producing mouse mutants useful in studying a wide range of diseases, developmental mechanisms, behavior, and physiology. By techniques described in Chapter 9, it is possible to eliminate or modify the function of a specific gene in ES cells (see Figure 9-38). Then the mutated ES cells can be employed to produce mice with a gene knockout (see Figure 9-39). Analysis of the effects caused by deleting or modifying a gene in this way often provides clues about the normal function of the gene and its encoded protein.

Tissues Are Maintained by Associated Populations of Stem Cells

Many differentiated cell types are sloughed from the body or have life spans that are shorter than that of the organism. Disease and trauma also can lead to loss of differentiated cells. Since these cells generally do not divide, they must be replenished from nearby stem-cell populations.

Our skin, for instance, is a multilayered epithelium (the epidermis) underlain by a layer of stem cells that give rise both to more of themselves and to keratinocytes, the major cell type in skin. Keratinocytes then move toward the outer surface, becoming increasingly flattened and filled with keratin intermediate filaments. It normally takes about 15-30 days for a newly "born" keratinocyte in the lowest layer to differentiate and move to the topmost layer. The "cells" forming the topmost layer are actually dead and are continually shed from the surface.

In contrast to epidermis, the epithelium lining the small intestine is a single cell thick (Figure 6-4). This thin layer keeps toxins and pathogens from entering our bodies and also transports nutrients essential for survival from the intestinal lumen into the body (Chapter 7). The cells of the intestinal epithelium continuously regenerate from a stem-cell population located deep in the intestinal wall in pits called crypts (Figure 22-4a). The stem cells produce precursor cells that proliferate and differentiate as they ascend the sides of crypts to form the surface layer of the finger-like gut projections called villi, across which intestinal absorption occurs. Pulse-chase labeling experiments have shown that the time from cell birth in the crypts to the loss of cells at the tip of the villi is only about 2 to 3 days (Figure 22-4b). Thus enormous numbers of cells must be produced continually to keep the epithelium intact. The production of new cells is precisely controlled: too little division would eliminate villi and lead to breakdown of the intestinal surface; too much division would create an excessively large epithelium and also might be a step toward cancer.

Specific signals are required for creating and maintaining stem-cell populations. In both the skin and the intestinal epithelium, stem-cell growth is regulated in part by p-catenin, a protein that helps link certain cell-cell junctions to the cyto-skeleton (see Figure 6-7) and also functions as a signal transducer in the Wnt pathway (see Figure 15-32). Activation of P-catenin moves cells from epidermis to hair cell fates. In contrast, removal of p-catenin specifically from the skin of engineered mice eliminates hair cell fates. Skin stem cells then form only epidermis, not hair cells. p-catenin thus acts as a switch between alternative cell fates. Overproduction of active p-catenin leads to excess proliferation of the intestinal epithelium. Blocking the function of p-catenin by interfering with the TCF transcription factor that it activates abolishes the stem cells in the intestine. It seems likely that Wnt signaling, or at least components of the intracellular pathway, is critical for forming, maintaining, or activating stem cells in a variety of tissues.

^ EXPERIMENTAL FIGURE 22-4 Regeneration of the intestinal epithelium from stem cells can be demonstrated in pulse-chase experiments. (a) Schematic drawing of the lining of the small intestine, which contains numerous villi formed from a column of cells. These epithelial cells are born near the base of pits (crypts) located between the villi. Located at the very bottom of crypts are Paneth cells, a type of support cell; just above these are four to six stem cells, which divide about once a day, forming precursor cells that also actively divide. As the differentiated cells enter the epithelium of a villus, they stop dividing and begin taking up nutrients from the gut. (b) Results from a pulse-chase experiment in which radioactively labeled thymidine (the pulse) was added to a tissue culture of the intestinal epithelium. Dividing cells incorporated the labeled thymidine into their newly synthesized DNA. The labeled thymidine was washed away and replaced with nonlabeled thymidine (the chase) after a brief period; cells that divided after the chase did not become labeled. These micrographs show that 40 minutes after labeling, all the label is in cells near the base of the crypt. At later times, the labeled cells are seen progressively farther away from their point of birth in the crypt. Cells at the top are shed. This process ensures contant replenishment of the gut epithelium with new cells. [Part (a) adapted from C. S. Potten, 1998, Philos. Trans. R. Soc. London, Ser. B 353:821. Part (b) courtesy of C. S. Potten, from P Kaur and C. S. Potten, 1986, Cell Tiss. Kinet. 19:601.]

Direction of cell migration

Direction of cell migration

► Differentiated region

► Proliferative region

Stem cells

Stem cells

► Differentiated region

► Proliferative region

Stem cell region

Paneth cells

Villi

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