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T and B cells of the immune system tinal stem cells in crypts. Numerous extracellular growth factors called cytokines regulate proliferation and differentiation of the precursor cells for various blood-cell lineages. For example, erythropoietin can activate several different intracellular signal-transduction pathways, leading to changes in gene expression that promote formation of erythrocytes (see Figure 14-7).

The hematopoietic lineage originally was worked out by injecting the various types of precursor cells into mice whose precursor cells had been wiped out by irradiation. By observing which blood cells were restored in these transplant experiments, researchers could infer which precursors or terminally differentiated cells (e.g., erythrocytes, monocytes) arise from a particular type of precursor. The first step in these experiments was separation of the different types of hematopoietic precursors. This is possible because each type produces unique combinations of cell-surface proteins that can serve as type-specific markers. If bone marrow extracts are treated with fluorochrome-labeled antibodies for these markers, cells with different surface markers can be separated in a fluorescence-activated cell sorter (see Figure 5-34).

To date, bone marrow transplants represent the most successful and widespread use of stem cells in medicine. The stem cells in the transplanted marrow can generate new, functional blood cells in patients with certain hereditary blood diseases and in cancer patients who have received irradiation and/or chemotherapy, both of which destroy the bone marrow cells as well as cancer cells. Recent work is directed at exploring whether embryonic stem cells can be induced to differentiate into cells types that would be useful therapeutically. For example, mouse stem cells treated with inhibitors of phosphatidylinositol-3 ki-nase, a regulator in one of the phosphoinositide signaling pathways (Chapter 14), turn into cells that resemble pancreatic p cells in their production of insulin, their sensitivity to glucose levels, and their aggregation into structures reminiscent of pancreas structures. Implantation of these cells into diabetic mice restored their growth, weight, glucose levels, and survival rates to normal. I

Stem cells in plants are located in meristems, populations of undifferentiated cells found at the tips of growing shoots. Shoot apical meristems (SAMs) produce leaves and shoots, and of course more stem cells that constitute the nearly immortal meristems. Meristems can persist for thousands of years in long-lived species such as redwood trees and bristlecone pines. As a plant grows, the cells "left behind" the meristems are encased in rigid cell walls and can no longer grow. SAMs can split to form branches, each branch with its own SAM, or be converted into floral meristems (Figure 22-6). Floral meristems give rise to the four floral organs—sepals, stamens, carpels, and petals—that form flowers. Unlike SAMs, floral meristems are gradually depleted as they give rise to the floral organs.

Numerous genes have been found to regulate the formation, maintenance, and properties of meristems. Many of these genes encode transcription factors that direct progeny of stem cells down different paths of differentiation. For instance, a hierarchy of regulators, particularly transcription factors, controls the separation of differentiating cells from SAMs as leaves form; similarly, three types of regulators control formation of the floral organs from floral meristems (Chapter 15). In both cases, a cascade of gene interactions occurs, with earlier transcription factors causing production of later ones. At the same time, cells are dividing and the differentiating ones are spreading away from their original birth sites. I

▲ FIGURE 22-6 Cell fates in meristems of Arabidopsis. In these longitudinal sections through a shoot apical meristem, cell nuclei are revealed by staining with propidium iodide, which binds to DNA. (a) The shoot apical meristem (SAM) produces shoots, leaves, and more meristem. Flower production occurs when the meristem switches from leaf/shoot production to flower production, concomitant with an increase in the number of meristem cells to form floral meristems (FMs), as shown here. (b) Cells in a SAM exhibit different fates and behaviors. Cells divide rapidly in the peripheral zone (PZ) to produce leaves and in the rib zone (Rib) to produce central shoot structures. Cells in the central zone (CZ) divide more slowly, producing an ongoing source of meristem and contributing cells to the PZ and Rib. (c) The layers of the meristem, colored here, are each derived (cloned) from the same precursor cell. The fates of cells in different positions in the L2 layer are shown color-coded in part (d). Scale bars, 50 ^m. [Parts (a)-(c) from E. Meyerowitz, 1997, Cell 88:299; micrographs courtesy of Elliot Meyerowitz. Part (d) after C. Wolpert et al., 2002, Principles of Development, 2d ed. (Oxford: Oxford University Press).]

Cell Fates Are Progressively Restricted During Development

The eight cells resulting from the first three divisions of a mammalian zygote (fertilized egg) all look the same. As demonstrated experimentally in sheep, each of the cells has the potential to give rise to a complete animal. Additional divisions produce a mass, composed of «64 cells, that separates into two cell types: trophectoderm, which will form extra-embryonic tissues like the placenta, and the inner cell mass, which gives rise to the embryo proper. The inner cell mass eventually forms three germ layers, each with distinct fates. One layer, the ectoderm, will make neural and epidermal cells; another, the mesoderm, will make muscle and connective tissue; the third layer, the endoderm, will make gut ep-ithelia (Figure 22-7). This conclusion is based on experiments with chimeric animals composed of chicken and quail cells. Embryos composed of cells from both bird species develop fairly normally, yet the cells derived from each donor are distinguishable under the microscope. Thus the contributions of the different donor cells to the final bird can be ascertained. If cells from one germ layer are transplanted into one of the other layers, they do not give rise to cells appropriate to their new location.

Once the three germ layers are established, they subsequently divide into cell populations with different fates. For instance, the ectoderm becomes divided into those cells that are precursors to the skin epithelium and those that are precursors to the nervous system. There appears to be a progressive restriction in the range of cell types that can be formed from stem cells and precursor cells as development proceeds. An early embryonic stem cell, as we've seen, can form every type of cell, an ectodermal cell has a choice between neural and epidermal fates, while a keratinocyte precursor can form skin but not neurons.

Another restriction that occurs early in animal development is the setting aside of cells that will form the germ line, that is, the stem cells and precursor cells that eventually will give rise to eggs in a female and sperm in a male. Only the genome of the germ line will ever be passed on to progeny. The setting aside of germ-line cells early in development has been hypothesized to protect chromosomes from damage by reducing the number of rounds of replication they undergo or by allowing special protection of the cells that are critical to heredity. Whatever the reason, the early segregation of the germ line is widespread (though not universal) among animals. In contrast, plants do nothing of the sort; most meristems can give rise to germ-line cells.

One consequence of the early segregation of germ-line cells is that the loss or rearrangement of genes in somatic cells would not affect the inherited genome of a future zygote. Although segments of the genome are rearranged and lost during development of lymphocytes from hematopoi-etic precursors, most somatic cells seem to have an intact genome, equivalent to that in the germ line. Evidence that at least some somatic cells have a complete and functional genome comes from the successful production of cloned an-

imals by nuclear-transfer cloning. In this procedure, the nucleus of an adult (somatic) cell is introduced into an egg that lacks its nucleus; the manipulated egg, which contains the diploid number of chromosomes and is equivalent to a zygote, then is implanted into a foster mother. The only source of genetic information to guide development of the embryo is the nuclear genome of the donor somatic cell. The frequent failure of such cloning experiments, however, raises

Epiblast

Amnioblasts

Epiblast

Amnioblasts

Yolk sac

Invaginating mesoderm cells

Hypoblast

Yolk sac

Invaginating mesoderm cells

Hypoblast

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