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Cell proliferation is fundamental to development, main- tenance of steady-state tissue homeostasis, and replace- ment of dead or damaged cells. The key elements of cellular proliferation are accurate DNA replication accom- panied by the coordinated synthesis of all other cellular constituents, followed by equal apportionment of DNA and other cellular constituents (e.g., organelles) to daugh- ter cells through mitosis and cytokinesis. #331 в контекст | | |
The sequence of events that results in cell division is called the cell cycle. The cell cycle consists of G1 (pre- synthetic growth), S (DNA synthesis), G2 (premitotic growth), and M (mitotic) phases; quiescent cells that are not actively cycling are in the G0 state. (Fig. 1.17). Cells can enter G1 either from the G0 quiescent cell pool or after completing a round of mitosis. Each stage requires completion of the previous step, as well as activation of necessary factors (see later); nonfidelity of DNA replica- tion or cofactor deficiency results in arrest at the various transition points. #332 в контекст | | |
The cell cycle is regulated by numerous activators and inhibitors. Cell-cycle progression is driven by proteins called cyclins—named for the cyclic nature of their pro- duction and degradation—and cyclin-associated enzymes called cyclin-dependent kinases (CDKs) (Fig. 1.18). CDKs acquire the ability to phosphorylate protein substrates (i.e., kinase activity) by forming complexes with the relevant cyclins. Transiently increased synthesis of a particular cyclin leads to increased kinase activity of the appropriate CDK binding partner; as the CDK completes its round of phosphorylation, the associated cyclin is degraded and the CDK activity abates. Thus, as cyclin levels rise and fall, the activity of associated CDKs likewise waxes and wanes. #333 в контекст | | |
More than 15 cyclins have been identified; cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDKs. The cell cycle thus resembles a relay race in which each leg is regulated by a distinct set of cyclins: as one collection of cyclins leaves the track, the next set takes over. #334 в контекст | | |
Embedded in the cell cycle are surveillance mechanisms primed to sense DNA or chromosomal damage. These quality-control checkpoints ensure that cells with genetic imperfections do not complete replication. Thus, the G1-S checkpoint monitors the integrity of DNA before irrevers- ibly committing cellular resources to DNA replication. Later in the cell cycle, the G2-M check point ensures that there has been accurate DNA replication before the cell actually divides. When cells do detect DNA irregularities, checkpoint activation delays cell-cycle progression and triggers DNA repair mechanisms. If the genetic derange- ment is too severe to be repaired, the cells either undergo #335 в контекст | | |
apoptosis or enter a nonreplicative state called senescence— primarily through p53-dependent mechanisms (see later). #336 в контекст | | |
Enforcing the cell-cycle checkpoints is the job of CDK inhibitors (CDKIs); they accomplish this by modulating CDK-cyclin complex activity. There are several different CDKIs: #337 в контекст | | |
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One family of CDKIs—composed of three proteins called p21 (CDKN1A), p27 (CDKN1B), and p57 (CDKN1C)— broadly inhibits multiple CDKs #339 в контекст | | |
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Another family of CDKIs has selective effects on cyclin CDK4 and cyclin CDK6; these proteins are called p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D) #341 в контекст | | |
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Defective CDKI checkpoint proteins allow cells with damaged DNA to divide, resulting in mutated daughter cells at risk for malignant transformation #343 в контекст | | |
An equally important aspect of cell growth and division is the biosynthesis of other cellular components needed to make two daughter cells, such as membranes and organ- elles. Thus when growth factor receptor signaling stimu- lates cell-cycle progression, it also activates events that promote changes in cellular metabolism that support growth. Chief among these is the Warburg effect, men- tioned earlier, marked by increased cellular uptake of glucose and glutamine, increased glycolysis, and (counter- intuitively) decreased oxidative phosphorylation. These changes are major elements of cancer-cell growth and are discussed in greater detail in Chapter 6. #344 в контекст | | |
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Not all stem cells are created equal. During develop- ment, totipotent stem cells can give rise to all types of differentiated tissues; in the mature organism, adult stem cells in various tissues only have the capacity to replace damaged cells and maintain cell populations within the tissues where they reside. There also are populations of stem cells between these extremes with varying capacities to differentiate into multiple cell lineages. Thus, depend- ing on the source and stage of development, there may be limits on the cell types that a stem cell population can generate. #346 в контекст | | |
In normal tissues (without neoplasia, degeneration, or healing), there is a homeostatic equilibrium between the replication, self-renewal, and differentiation of stem cells and the death of the mature, fully differenti- ated cells (Fig. 1.19). The dynamic relationship between stem cells and terminally differentiated parenchyma is nicely exemplified by the continuously dividing epithe- lium 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. #347 в контекст | | |
Under conditions of homeostasis, stem cells are char- acterized by two important properties: #348 в контекст | | |
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Self-renewal, which permits stem cells to maintain their numbers. Self-renewal may follow asymmetric or sym- metric division. #350 в контекст | | |
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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. #352 в контекст | | |
Although there is a tendency in the scientific literature to partition stem cells into several different subsets, funda- mentally there are only two varieties: #353 в контекст | | |
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Embryonic stem cells (ES cells) are the most undifferenti- ated. They are present in the inner cell mass of the 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 main- tained for extended periods without differentiating; thereafter, appropriate culture conditions allow them to form specialized cells of all three germ cell layers, including neurons, cardiac muscle, liver cells, and pan- #355 в контекст | | |
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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 spe- cialized 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). #358 в контекст | | |
Adult stem cells have a limited repertoire of differ- entiated 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., endothe- lium) cell turnover, the adult stem cells in any given tissue can usually only produce cells that are normal constituents of that tissue. #359 в контекст | | |
Hematopoietic stem cells are the most extensively studied; they continuously replenish all the cellular ele- ments 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). #360 в контекст | | |
Besides hematopoietic stem cells, the bone marrow (and notably, other tissues such as fat) also contains a popula- tion of mesenchymal stem cells. These are multipotent cells that can differentiate into a variety of stromal cells includ- ing chondrocytes (cartilage), osteocytes (bone), adipocytes (fat), and myocytes (muscle). Because these cells can be expanded to large numbers, they represent a potential means of manufacturing the stromal scaffolding needed for tissue regeneration. #361 в контекст | | |
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The ability to identify, isolate, expand, and transplant #363 в контекст | | |
stem cells has given birth to the new field of regenerative medicine. Theoretically, the differentiated progeny of ES or adult stem cells can be used to repopulate damaged tissues or to construct entire organs for replacement. In particular, there is considerable excitement about the ther- apeutic opportunities for restoring damaged tissues that have low intrinsic regenerative capacity, such as myocar- dium after a myocardial infarct or neurons after a stroke. Unfortunately, despite an improving ability to purify and expand stem cell populations, much of the initial enthusi- asm has been tempered by difficulties encountered in introducing and functionally integrating the replacement cells into sites of damage. #364 в контекст | | |
More recently it has been possible to generate pluripo- tential cells, resembling ES cells, that are derived from the patient into whom they will be implanted. To accomplish this, a handful of genes have been identified whose prod- ucts can—remarkably—reprogram somatic cells to achieve the “stem-ness” of ES cells. When such genes are intro- duced into fully differentiated cells (e.g., fibroblasts), induced pluripotent stem cells (iPS cells) are generated (Fig. 1.22), albeit at low frequency. Because these cells are derived from the patient, their differentiated progeny (e.g., insulin-secreting β-cells in a patient with diabetes) can be engrafted without eliciting an immunologically mediated rejection reaction that would occur if the differentiated cells were derived from ES cells obtained from another donor. #365 в контекст | | |
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This survey of selected topics in cell biology serves as a basis for our later discussions of pathology, and we will refer back to it throughout the book. Students should, however, remember that this summary is intentionally brief, and more information about some of the fascinating topics reviewed here can be readily found in textbooks devoted to cell and molecular biology. #367 в контекст | | |
