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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.
The examples we have discussed so far represent a small selection of the tissues and cell types that derive from the outer layer of the embryo—the ectoderm. They are enough, however, to give a sense of the amazing variety of ways in which this epithelium becomes specialized for different purposes, and to show how widely adult cells can differ in their lifestyles. The inmost layer of the embryo—the endoderm, forming the primitive gut tube—gives rise to another whole zoo of cell types lining the digestive tract and its appendages. We begin with the lungs.
The airways of the lungs are formed by repeated branching of a system of tubes that originated in the embryo from an outpocketing of the gut lining, as discussed in Chapter 21. Repeated tiers of branching terminate in several hundred million air-filled sacs—the alveoli. Alveoli have thin walls, closely apposed to the walls of blood capillaries so as to allow exchange of O2 and CO2 with the blood stream (Figure 22-17).
Alveoli in the lung. (A) Scanning electron micrograph at low magnification, showing the sponge-like texture created by the many air-filled alveoli. A bronchiole (small tubular airway) is seen at the top, communicating with the alveoli. (B) Transmission (more...)
To survive, the cells lining the alveoli must remain moist. At the same time, they must serve as a gas container that can expand and contract with each breath in and out. This creates a problem. When two wet surfaces touch, they become stuck together by surface tension in the layer of water between them—an effect that operates more powerfully the smaller the scale of the structure. There is a risk, therefore, that the alveoli may collapse and be impossible to reinflate. The problem is solved by the presence of two types of cells in the lining of the alveoli. Type I alveolar cells cover most of the wall: they are thin and flat (squamous) to allow gas exchange. Type II alveolar cells are interspersed among them. These are plump and secrete surfactant, a phospholipid-rich material that forms a film on the free water surfaces and reduces surface tension, making the alveoli easy to reinflate even if they collapse. The production of adequate amounts of surfactant in the fetus, starting at about 5 months of pregnancy in humans, marks the beginning of the possibility of independent life. Premature babies born before this stage are unable to inflate their lungs and breathe; those born after it can do so and, with intensive care, can survive.
Higher up in the airways one finds different combinations of cell types, serving different purposes. The air we breathe is full of dust, dirt, and air-borne microorganisms. To keep the lungs clear and healthy, this debris must be constantly swept out. To perform this task, the larger airways are lined by a relatively thick respiratory epithelium (Figure 22-18). This includes three differentiated cell types: goblet cells (so named because of their shape), which secrete mucus, ciliated cells, with cilia that beat, and a small number of endocrine cells, secreting serotonin and peptides that act as local mediators. These signal molecules affect nerve endings and other neighboring cells in the respiratory tract, so as to help regulate the rate of mucus secretion and ciliary beating, the contraction of surrounding smooth muscle cells that can constrict the airways, and other functions. Basal cells are also present, and serve as stem cells for renewal of the epithelium.
Respiratory epithelium. The goblet cells secrete mucus, which forms a blanket over the tops of the ciliated cells. The regular, coordinated beating of the cilia sweeps the mucus up and out of the airways, carrying any debris that is stuck to it. The mechanism (more...)
The mucus secreted by the goblet cells forms a viscoelastic blanket about 5 μm thick over the tops of the cilia. The cilia, all beating in the same direction, at a rate of about 12 beats per second, sweep the mucus out of the lungs, carrying with it the debris that has become stuck to it. This conveyor belt for the removal of rubbish from the lungs is called the mucociliary escalator. Of course, some inhaled particles may reach the alveoli themselves, where there is no escalator. Here, the unwanted matter is removed by yet another class of specialized cells, macrophages, which roam the lungs and engulf foreign matter and kill and digest bacteria. Many millions of macrophages, loaded with debris, are swept out of the lungs every hour on the mucociliary escalator.
At the upper end of the respiratory tract, the wet mucus-covered respiratory epithelium gives way abruptly to stratified squamous epithelium. This cell sheet is structured for mechanical strength and protection, and, like epidermis, it consists of many layers of flattened cells densely packed with keratin. It differs from epidermis in that it is kept moist and its cells retain their nucleus even in the outermost layers. Abrupt boundaries of epithelial cell specialization, such as that between the mucous and the stratified squamous epithelium of the respiratory tract, are also found in other parts of the body, but very little is known about how they are created and maintained.
Only air-breathing vertebrates have lungs, but all vertebrates, and almost all invertebrate animals, have a gut—that is, a digestive tract lined with cells specialized for the digestion of food and absorption of the nutrient molecules released by the digestion. These two activities are hard to carry on at the same time, as the processes that digest food in the lumen of the gut are liable also to digest the lining of the gut itself, including the cells that absorb the nutrients. The gut uses several strategies to solve the problem.
The fiercest digestive processes, involving acid hydrolysis as well as enzyme action, are conducted in a separate reaction vessel, the stomach. The products are then passed on to the small intestine, where the nutrients are absorbed and enzymatic digestion continues, but at a neutral pH. The different regions of the gut lining consist of correspondingly different mixtures of cell types. The stomach epithelium includes cells that secrete acid, and other cells that secrete digestive enzymes that work at acid pH. Conversely, glands (in particular the pancreas) that discharge into the initial segment of the small intestine contain cells that secrete bicarbonate to neutralize the acidity, along with other cells that secrete digestive enzymes that work at neutral pH. The lining of the intestine, downstream from the stomach, contains both absorptive cells and cells specialized for secretion of mucus, which covers the epithelium with a protective coat. In the stomach, too, the most exposed surfaces are lined with mucous cells. And, in case these measures are not enough, the whole lining of the stomach and intestine is continually renewed and replaced by freshly generated cells, with a turnover time of a week or less.
The renewal process has been studied best in the small intestine (Figure 22-19). The lining of the small intestine (and of most other regions of the gut) is a single-layered epithelium. This epithelium covers the surfaces of the villi that project into the lumen, and it lines the crypts that descend into the underlying connective tissue. Dividing stem cells lie in a protected position in the depths of the crypts. These generate four types of differentiated progeny (Figure 22-20): (1) absorptive cells (also called brush-border cells), with densely packed microvilli on their exposed surfaces to increase their active surface area; (2) goblet cells (as in respiratory epithelium), secreting mucus; (3) Paneth cells, forming part of the innate immune defense system (discussed in Chapter 25) and secreting (along with some growth factors) cryptdins—proteins of the defensin family that kill bacteria (see Figure 25-39); and (4) enteroendocrine cells, of more than 15 different subtypes, secreting serotonin and peptide hormones, such as cholecystokinin, that act on neurons and other cell types in the gut wall and regulate the growth, proliferation and digestive activities of cells of the gut and other tissues; many of these gut hormones function also as neuropeptide signal molecules in the nervous system.
Renewal of the gut lining. (A) The pattern of cell turnover and the proliferation of stem cells in the epithelium that forms the lining of the small intestine. The arrow shows the general upward direction of cell movement onto the villi, but some cells, (more...)
The four main differentiated cell types found in the epithelial lining of the small intestine. All of these are generated from undifferentiated multipotent stem cells living near the bottoms of the crypts (see Figure 22-19). The microvilli on the apical (more...)
The absorptive, goblet, and enteroendocrine cells travel mainly upward from the stem-cell region, by a sliding movement in the plane of the epithelial sheet, to cover the surfaces of the villi. As in the epidermis, there is a transit amplifying stage of cell proliferation: on their way out of the crypt, the precursor cells, already committed to differentiation, go through four to six rapid divisions before they stop dividing and differentiate terminally. Within 2–5 days (in the mouse) after emerging from the crypts, the cells reach the tips of the villi, where they undergo the initial stages of apoptosis and are finally discarded into the gut lumen. The Paneth cells are produced in much smaller numbers and have a different migration pattern. They stay down at the bottom of the crypts, where they too are continually replaced, although not so rapidly, persisting for about 20 days (in the mouse) before undergoing apoptosis and being phagocytosed by their neighbors.
The driving force for the movements of the gut epithelial cells is still a mystery. Their different patterns of migration may be controlled by cell-type-specific responses to molecular cues in the basal lamina on which they sit. Different regions of the lamina are rich in different types of laminin: α1 and α2 laminin subunits are concentrated in the basal lamina of the crypts, while α5 is in the basal lamina of the villi, in a concentration gradient with its maximum at the villus tip.
What controls whether a gut stem cell retains its stem-cell character or embarks on differentiation? What drives the diversification of the stem cell progeny to produce four different cell types? Despite their importance in normal life and in many diseases, including common forms of cancer, the answers are unknown. There are, however, some clues.
The production of enteroendocrine cells, for example, depends on a cell-fate choice governed by the Notch signaling pathway in much the same way as the production of neurons in the embryonic central nervous system (discussed in Chapter 21). Mutations that block Notch signaling cause enteroendocrine cells to be produced in excess at the expense of other cell types, at least in the embryo.
Other experiments indicate that the Wnt signaling pathway has a crucial role in maintaining the stem cell population of the gut. Mice deficient in one of the LEF-1/TCF family of gene regulatory proteins involved in Wnt signaling (discussed in Chapter 15) provide one line of evidence: villi covered with differentiated cells are formed in the mutant fetus, but the epithelium cannot be renewed, because no crypts form and no proliferating stem cells are retained, and the mouse dies soon after birth. Conversely, in adult life, overactivation of the same signaling pathway by mutations in another gene (the APC gene—see Figure 15-72) result in an overproliferation of crypt cells and frequently lead to cancer, as we shall see in Chapter 23. All this suggests that in the gut, as in the epidermis, Wnt signaling has a key role in either maintaining stem cells as stem cells or controlling their proliferation.
As we have just seen, the functions of the gut are divided between a variety of cell types. Some cells are specialized for the secretion of hydrochloric acid, others for the secretion of enzymes, others for the absorption of nutrients, and so on. Some of these cell types are closely intermingled in the wall of the gut, whereas others are segregated in large glands that communicate with the gut and originate in the embryo as outgrowths of the gut epithelium.
The liver is the largest of these glands. It develops at a site where a major vein runs close to the wall of the primitive gut tube, and the adult organ retains a special relationship with the blood. Cells in the liver that derive from the primitive gut epithelium—the hepatocytes—are arranged in interconnected sheets and cords, with blood-filled spaces called sinusoids running between them (Figure 22-21). The blood is separated from the surface of the hepatocytes by a single layer of flattened endothelial cells that covers the exposed faces of the hepatocytes. This structure facilitates the chief functions of the liver, which center on the exchange of metabolites between hepatocytes and the blood.
The structure of the liver. (A) A scanning electron micrograph of a portion of the liver, showing the irregular sheets and cords of hepatocytes and the many small channels, or sinusoids, for the flow of blood. The larger channels are vessels that distribute (more...)
The liver is the main site at which nutrients that have been absorbed from the gut and then transferred to the blood are processed for use by other cells of the body. It receives a major part of its blood supply directly from the intestinal tract (via the portal vein). Hepatocytes are responsible for the synthesis, degradation, and storage of a vast number of substances. They play a central part in the carbohydrate and lipid metabolism of the body as a whole, and they secrete most of the protein found in blood plasma. At the same time, the hepatocytes remain connected with the lumen of the gut via a system of minute channels (or canaliculi) and larger ducts (see Figure 22-21B,C) and secrete into the gut by this route both waste products of their metabolism and an emulsifying agent, bile, which helps in the absorption of fats. Hepatocytes are big cells, and about 50% of them (in an adult human) are polyploid, with two, four, eight, or even more times the normal diploid quantity of DNA per cell.
In contrast to the rest of the digestive tract, there seems to be remarkably little division of labor within the population of hepatocytes. Each hepatocyte seems able to perform the same broad range of metabolic and secretory tasks. These fully differentiated cells can also divide repeatedly, when the need arises, as we explain next.
The liver illustrates in a striking way one of the great unsolved problems of developmental and tissue biology: what determines the size of an organ of the body, or the quantity of one type of tissue relative to another? For different organs, the answers are almost certainly different, but there is scarcely any case in which the mechanism is well understood.
Hepatocytes normally live for a year or more and are renewed at a slow rate. Even in a slowly renewing tissue, however, a small but persistent imbalance between the rate of cell production and the rate of cell death would lead to disaster. If 2% of the hepatocytes in a human divided each week but only 1% died, the liver would grow to exceed the weight of the rest of the body within 8 years. Homeostatic mechanisms must operate to adjust the rate of cell proliferation and/or the rate of cell death so as to keep the organ at its normal size. This size, moreover, needs to be matched to the size of the rest of the body. Indeed, when the liver of a small dog is grafted into a large dog, it rapidly grows to almost the size appropriate to the host; conversely, when the liver is grafted from a large dog into a small one, it shrinks.
Direct evidence for the homeostatic control of liver cell proliferation comes from experiments in which large numbers of hepatocytes are removed surgically or are intentionally killed by poisoning with carbon tetrachloride. Within a day or so after either sort of damage, a surge of cell division occurs among the surviving hepatocytes, and the lost tissue is quickly replaced. (If the hepatocytes themselves are totally eliminated, another class of cells, located in the bile ducts, can serve as stem cells for the genesis of new hepatocytes, but usually there is no need for this.) If two-thirds of a rat's liver is removed, for example, a liver of nearly normal size can regenerate from the remainder by hepatocyte proliferation within about 2 weeks. Many molecules have been implicated in the triggering of this reaction. One of the most important is a protein called hepatocyte growth factor. It stimulates hepatocytes to divide in culture, and its production increases steeply (by poorly understood mechanisms) in response to liver damage.
The balance between cell births and cell deaths in the adult liver (and other organs too) does not depend exclusively on the regulation of cell proliferation: cell survival controls also play a part. If an adult rat is treated with the drug phenobarbital, for example, hepatocytes are stimulated to divide, causing the liver to enlarge. When the phenobarbital treatment is stopped, hepatocyte cell death greatly increases until the liver returns to its original size, usually within a week or so. The mechanism of this type of cell survival control is unknown, but it has been suggested that hepatocytes, like most vertebrate cells, depend on signals from other cells for their survival and that the normal level of these signals can support only a certain standard number of hepatocytes. If the number of hepatocytes rises above this (as a result of phenobarbital treatment, for example), hepatocyte death will automatically increase to bring their number back down. It is not known how the appropriate levels of survival factors are maintained.
The lung performs a simple function—gas exchange—but its housekeeping systems are complex. Surfactant-secreting cells help to keep the alveoli from collapsing. Macrophages constantly scour the alveoli for dirt and microorganisms. A mucociliary escalator formed by mucus-secreting goblet cells and beating ciliated cells sweeps debris out of the airways.
In the gut, where more potentially damaging chemical processes occur, the absorptive epithelium is kept in good repair by constant rapid renewal. In the small intestine, stem cells in the crypts generate new absorptive, goblet, enteroendocrine, and Paneth cells, replacing most of the epithelial lining of the intestine every week. The diverse fates of the stem-cell progeny are controlled, in part at least, by the Notch signaling pathway, while the Wnt pathway is required to maintain the stem-cell population.
The liver is a more protected organ, but it too can rapidly adjust its size up or down by cell proliferation or cell death when the need arises. Differentiated hepatocytes remain able to divide throughout life, showing that a specialized class of stem cells is not always needed for tissue renewal.
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