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Integrating cells into tissues
Cells evolved as single, free-living organisms, but natural selection favoured more complex communities of cells, multicellular organisms, where groups of cells specialize during development to carry out specific functions for the body as a whole. This allowed the emergence of larger organisms with greater control over their internal environment and the evolution of highly specialized organic structures such as the brain. The human body contains more than 200 different cell types, sharing the same genome but with different patterns of gene expression.
Some cells in the body are essentially migratory, but most exist as cellular aggregates in which individual cells carry out similar or closely related functions in a coordinated manner. These aggregates are termed tissues, and can be classified into a fairly small number of broad categories on the basis of their structure, function and molecular properties. On the basis of their structure, most tissues are divided into four major types: epithelia, connective or supporting tissue, muscle and nervous tissue. Epithelia are continuous layers of cells with little intercellular space, which cover or line surfaces, or have been so derived. In connective tissues, the cells are embedded in an extracellular matrix, which, typically, forms a substantial and important component of the tissue. Muscle consists largely of specialized contractile cells. Nervous tissue consists of cells specialized for conducting and transmitting electrical and chemical signals and the cells that support this activity.
There is molecular evidence that this structure-based scheme of classification has validity. Thus the intermediate filament proteins characteristic of all epithelia are keratins ( ); those of connective tissue are vimentins; those of muscle are desmins; and those of nervous tissue are neurofilament and glial fibrillary acidic proteins. However, cells such as myofibroblasts, neuroepithelial sensory receptors and ependymal cells of the central nervous system have features of more than one tissue type. Despite its anomalies, the scheme is useful for descriptive purposes; it is widely used and will be adopted here.
In this chapter, two of the major tissue categories, epithelia and general connective and supporting tissues, will be described. Specialized skeletal connective tissues, i.e. cartilage and bone, together with skeletal muscle, are described in detail in Chapter 5 as part of the musculoskeletal system overview. Smooth muscle and cardiac muscle are described in Chapter 6 . Nervous system tissues are described in Chapter 3 . Specialized defensive cells, which also form a migrant population within the general connective tissues, are considered in more detail in Chapter 4 , with blood, lymphoid tissues and haemopoiesis.
Epithelia
The term epithelium is applied to the layer or layers of cells that cover the body surfaces or line the body cavities that open on to it. The fate of embryonic epithelial populations is illustrated in Fig. 2.3 . Epithelia function generally as selective barriers that facilitate, or inhibit, the passage of substances across the surfaces they cover. In addition, they may: protect underlying tissues against dehydration, chemical or mechanical damage; synthesize and secrete products into the spaces that they line; and function as sensory surfaces. In this respect, many features of nervous tissue can be regarded as those of a modified epithelium and the two tissue types share an origin in embryonic ectoderm.
Epithelia ( Fig. 2.1 ) are predominantly cellular and the little extracellular material they possess is limited to the basal lamina. Intercellular junctions, which are usually numerous, maintain the mechanical cohesiveness of the epithelial sheet and contribute to its barrier functions. A series of three intercellular junctions forms a typical epithelial junctional complex: in sequence from the apical surface, this consists of a tight junctional zone, an adherent (intermediate) junctional zone and a region of discrete desmosome junctions. Epithelial cell shape is most usually polygonal and partly determined by cytoplasmic features such as secretory granules. The basal surface of an epithelium lies in contact with a thin layer of filamentous protein and proteoglycan termed the basal lamina, which is synthesized predominantly by the epithelial cells. The basal lamina is described on p. 35 .
Epithelia can usually regenerate when injured. Indeed, many epithelia continuously replace their cells to offset cell loss caused by mechanical abrasion (reviewed in ). Blood vessels do not penetrate typical epithelia and so cells receive their nutrition by diffusion from capillaries of neighbouring connective tissues. This arrangement limits the maximum thickness of living epithelial cell layers. Epithelia, together with their supporting connective tissue, can often be removed surgically as one layer, which is collectively known as a membrane. Where the surface of a membrane is moistened by mucous glands it is called a mucous membrane or mucosa (see p. 41 ), whereas a similar layer of connective tissue covered by mesothelium is called a serous membrane or serosa.
Classification
Epithelia can be classified as unilaminar (single-layered, simple), in which a single layer of cells rests on a basal lamina; or multilaminar, in which the layer is more than one cell thick. The latter includes: stratified squamous epithelia, in which flattened superficial cells are constantly replaced from the basal layers; urothelium (transitional epithelium), which serves special functions in the urinary tract; and other multilaminar epithelia such as those lining the largest ducts of some exocrine glands, which, like urothelium, are replaced only very slowly under normal conditions. Seminiferous epithelium is a specialized multilaminar tissue found only in the testis.
Unilaminar (simple) epithelia
Unilaminar epithelia are further classified according to the shape of their cells, into squamous, cuboidal, columnar and pseudostratified types. Cell shape may, in some cases, be related to cell volume. Where little cytoplasm is present, there are generally few organelles and therefore there is low metabolic activity and cells are squamous or low cuboidal. Highly active cells, e.g. secretory epithelia, contain abundant mitochondria and endoplasmic reticulum, and are typically tall cuboidal or columnar. Unilaminar epithelia can also be subdivided into those that have special functions, such as those with cilia, numerous microvilli, secretory vacuoles (in mucous and serous glandular cells) or sensory features. Myoepithelial cells, which are contractile, are found as isolated cells associated with glandular structures, e.g. salivary and mammary glands.
Squamous epithelium
Simple squamous epithelium is composed of flattened, tightly apposed, polygonal cells (squames). This type of epithelium is described as tessellated when the cells have complex, interlocking borders rather than straight boundaries. The cytoplasm may in places be only 0.1 μm thick and the nucleus usually bulges into the overlying space ( Fig. 2.2A ). These cells line the alveoli of the lungs, where their surface area is huge and cytoplasmic volume correspondingly large, and they also form the outer capsular wall of renal corpuscles, the thin segments of the renal tubules and various parts of the inner ear. Because it is so thin, simple squamous epithelium allows rapid diffusion of gases and water across its surface; it may also engage in active transport, as indicated by the presence of numerous endocytic vesicles in these cells. Tight junctions (occluding junctions, zonulae occludentes) between adjacent cells ensure that materials pass primarily through cells, rather than between them.
Cuboidal and columnar epithelia
Cuboidal and columnar epithelia consist of regular rows of cylindrical cells ( Figs 2.2B – C ). Cuboidal cells are approximately square in vertical section, whereas columnar cells are taller than their diameter, and both are polygonal when sectioned horizontally. Commonly, microvilli are found on their free surfaces, considerably increasing the absorptive area, e.g. in the epithelia of the small intestine (columnar cells with a striated border of very regular microvilli), the gallbladder (columnar cells with a brush border of microvilli); proximal convoluted tubules of the kidney (large cuboidal to low columnar cells with brush borders); and the epididymis (columnar cells with extremely long microvilli, erroneously termed stereocilia).
Ciliated columnar epithelium lines most of the respiratory tract, except for the lower pharynx and vocal folds, and is pseudostratified ( Fig. 2.2D ) as far as the larger bronchioles. It also lines some of the tympanic cavity and auditory tube, the uterine tube and the efferent ductules of the testis. Submucosal mucous glands and mucosal goblet cells secrete mucus on to the luminal surface of much of the respiratory tract, and cilia sweep a layer of mucus, trapped dust particles and so on from the lung towards the pharynx in the mucociliary rejection current, which clears the respiratory passages of inhaled particles. Cilia in the uterine tube assist the passage of oocytes and fertilized ova to the uterus.
Some columnar cells are specialized for secretion, and aggregates of such cells may be described as glandular tissue. Their apical domains typically contain mucus- or protein-filled (zymogen) vesicles, e.g. mucin-secreting and chief cells of the gastric epithelium. Where mucous cells lie among non-secretory cells, e.g. in the intestinal epithelium, their apical cytoplasm and its secretory contents often expand to produce a characteristic cell shape, and they are known as goblet cells (see Fig. 2.2D ). For further details of glandular tissue, see p. 33 , and for the characteristics of mucus, see p. 42 .
Pseudostratified epithelium
Pseudostratified epithelium is a single-layered (simple) columnar epithelium in which nuclei lie at different levels in a vertical section (see Fig. 2.2D ). All cells are in contact with the basal lamina throughout their lifespan, but not all cells extend through the entire thickness of the epithelium. Some constitute an immature basal cell layer of smaller cells, which are often mitotic and able to replace damaged mature cells. Migrating lymphocytes and mast cells within columnar epithelia may also give a similar, pseudostratified appearance because their nuclei are found at different depths. Much of the ciliated lining of the respiratory tract is of the pseudostratified type, and so is the sensory epithelium of the olfactory area.
Sensory epithelia
Sensory epithelia are found in special sense organs of the olfactory, gustatory and vestibulocochlear receptor systems. All of these contain sensory cells surrounded by supportive non-receptor cells. Olfactory receptors are modified neurones and their axons pass directly to the brain, but the other types are specialized epithelial cells that synapse with terminals of afferent (and sometimes efferent) nerve fibres.
Myoepithelial cells
Myoepithelial cells (sometimes termed basket cells) are fusiform or stellate in shape ( Fig. 2.3 ), contain actin and myosin filaments, and contract when stimulated by nervous or endocrine signals. They surround the secretory portions and ducts of some glands, e.g. mammary, lacrimal, salivary, prostate and sweat glands, and lie between the basal lamina and the glandular or ductal epithelium. Their contraction assists the initial flow of secretion into larger conduits. Ultrastructurally, myoepithelial cells are similar to smooth muscle cells in the arrangement of their actin and myosin, but differ from them because they originate, like the glandular cells, from embryonic ectoderm or endoderm. They can be identified immunohistochemically on the basis of the co-localization of myofilament proteins (which signify their contractile function; Fig. 2.4 ) and keratin intermediate filaments (which accords with their epithelial lineage) ( ).
Multilaminar (stratified) epithelia
Multilaminar epithelia are found at surfaces subjected to mechanical damage or other potentially harmful conditions. They can be divided into those that continue to replace their surface cells from deeper layers, designated stratified squamous epithelia, and others in which replacement is extremely slow except after injury.
Stratified squamous epithelia
Stratified squamous epithelia are multilayered tissues in which the formation, maturation and loss of cells is continuous, although the rates of these processes can change, e.g. after injury. New cells are formed in the most basal layers by the mitotic division of stem cells and transit (or transient) amplifying cells. The daughter cells move more superficially, changing gradually from a cuboidal shape to a more flattened form, and are eventually shed from the surface as a highly flattened squame. Typically, the cells are held together by numerous desmosomes to form strong, contiguous cellular sheets that provide protection to the underlying tissues against mechanical, microbial and chemical damage. Stratified squamous epithelia may be broadly subdivided into keratinized and non-keratinized types.
Keratinized epithelium
Keratinized epithelium ( Fig. 2.5A ) is found at surfaces that are subject to drying or mechanical stresses, or are exposed to high levels of abrasion. These include the entire epidermis and the mucocutaneous junctions of the lips, nostrils, distal anal canal, outer surface of the tympanic membrane and parts of the oral lining (gingivae, hard palate and filiform papillae on the anterior part of the dorsal surface of the tongue). Their cells, keratinocytes, are described in more detail on p. 146 . A distinguishing feature of keratinized epithelia is that cells of the superficial layer, the stratum corneum, are anucleate, dead, flattened squames that eventually flake off from the surface. In addition, the tough keratin intermediate filaments become firmly embedded in a matrix protein. This unusual combination of strongly coherent layers of living cells and more superficial strata made of plates of inert, mechanically robust protein complexes, interleaved with water-resistant lipid, makes this type of epithelium an efficient barrier against different types of injury, microbial invasion and water loss.
Non-keratinized epithelium
Non-keratinized epithelium is present at surfaces that are subject to abrasion but protected from drying ( Fig. 2.5B ). These include: the buccal cavity (except for the areas noted above); oropharynx and laryngopharynx; oesophagus; part of the anal canal; vagina; distal uterine cervix; distal urethra; cornea; inner surfaces of the eyelids; and the vestibule of the nasal cavities. Cells go through the same transitions in general shape as are seen in the keratinized type, but they do not fill completely with keratin or secrete glycolipid, and they retain their nuclei until they desquamate at the surface. In sites where considerable abrasion occurs, e.g. parts of the buccal cavity, the epithelium is thicker and its most superficial cells may partly keratinize, so that it is referred to as parakeratinized, in contrast to the orthokeratinized state of fully keratinized epithelium. Diets deficient in vitamin A may induce keratinization of such epithelia, and excessive doses may lead to its transformation into mucus-secreting epithelium.
Stratified cuboidal and columnar epithelia
Two or more layers of cuboidal or low columnar cells ( Fig. 2.5C ) are typical of the walls of the larger ducts of some exocrine glands, e.g. the pancreas, salivary glands and the ducts of sweat glands, and they presumably provide more strength than a single layer. Parts of the male urethra are also lined by stratified columnar epithelium. The layers are not continually replaced by basal mitoses and there is no progression of form from base to surface, but they can repair themselves if damaged.
Urothelium (urinary or transitional epithelium)
Urothelium ( Fig. 2.5D ) is a specialized epithelium that lines much of the urinary tract and prevents its rather toxic contents from damaging surrounding structures. It extends from the ends of the collecting ducts of the kidneys, through the ureters and bladder, to the proximal portion of the urethra. In males it lines the urethra as far as the ejaculatory ducts, then becomes intermittent and is finally replaced by stratified columnar epithelium in the membranous urethra. In females it extends as far as the urogenital membrane.
The epithelium appears to be 4–6 cells thick and lines organs that undergo considerable distension and contraction. It can therefore stretch greatly without losing its integrity. In stretching, the cells become flattened without altering their positions relative to each other, because they are firmly connected by numerous desmosomes. However, the urothelium appears to be reduced to only 2–3 cells thick. The epithelium is called transitional because of the apparent transition from a stratified cuboidal epithelium to a stratified squamous epithelium, which occurs as it is stretched to accommodate urine, particularly in the bladder. The basal cells are basophilic and contain many ribosomes; they are uninucleate (diploid), and cuboidal when relaxed. More apically, they form large binucleate or, more often, polyploid uninucleate cells. The surface cells are the largest and may even be octoploid; in the relaxed state they typically bulge into the lumen as dome-shaped cells with a thickened, eosinophilic glycocalyx or cell coat. Their luminal surfaces are covered by a specialized plasma membrane in which plaques of intramembranous glycoprotein particles are embedded to stiffen the membrane. When the epithelium is relaxed, the surface area of the cells is reduced and the plaques are partially internalized by the hinge-like action of the more flexible interplaque membrane regions. The plaques re-emerge on to the surface when it is stretched.
Normally, cell turnover is very slow; cell division is infrequent and is restricted to the basal layer. However, when damaged, the epithelium regenerates quite rapidly ( ).
Seminiferous epithelium
Seminiferous epithelium is a highly specialized, complex stratified epithelium. It consists of a heterogeneous population of cells that form the lineage of the spermatozoa (spermatogonia, spermatocytes, spermatids), together with supporting cells (Sertoli cells). It is described in detail on page 1295 .
Glands
One of the features of many epithelia is their ability to alter the environment facing their free surfaces by the directed transport of ions, water or macromolecules. This is particularly well demonstrated in glandular tissue, in which the metabolism and structural organization of the cells are specialized for the synthesis and secretion of macromolecules, usually from the apical surface. Such cells may exist in isolation amongst other non-secretory cells of an epithelium, e.g. goblet cells in the absorptive lining of the small intestine, or may form highly coherent sheets of epithelium with a common secretory function, e.g. the mucous lining of the stomach and, in a highly invaginated structure, the complex salivary glands.
Glands are conventionally subdivided into exocrine glands and endocrine glands. Exocrine glands secrete, usually via a duct, onto surfaces that are continuous with the exterior of the body, including the gastrointestinal and respiratory tracts, urinary and genital ducts and their derivatives, and the skin. Endocrine glands are ductless and secrete hormones directly into interstitial fluid and thence the circulatory system, to be conveyed throughout the body to affect the activities of other cells. The suprarenal (adrenal) medulla and the neurohypophysis are neurosecretory.
Paracrine glandular cells are similar to endocrine cells but their secretions diffuse locally to cellular targets in the immediate vicinity: many are classed as neuroendocrine cells because they secrete molecules active elsewhere in the nervous system as neurotransmitters or neuromodulators. Modes of signalling by secretory cells are illustrated in Fig. 1.9 .
Exocrine glands
Types of secretory process
Secretory mechanisms vary. Secretions that are initially packaged into membrane-bound vesicles are conveyed to the cell surface, where they are discharged by exocytosis. This is merocrine secretion, which is by far the most common secretory mechanism, where vesicle membranes fuse with the plasma membrane to release their contents to the exterior ( Fig. 2.6 ). Specialized transmembrane molecules in the secretory vesicle wall recognize marker proteins on the cytoplasmic side of the plasma membrane and bind to them. This initiates interactions with other proteins that cause the fusion of the two membranes and the consequent release of the vesicle contents. The stimulus for secretion varies with the type of cell but often appears to involve a rise in intracellular calcium. Glands such as the simple sweat glands of the skin, where ions and water are actively transported from plasma as an exudate, were once classified as eccrine glands. They are now known to synthesize and secrete small amounts of protein by a merocrine mechanism, and have been reclassified as merocrine glands.
In apocrine glands, some of the apical cytoplasm is pinched off with the contained secretions, which are stored in the cell as membrane-free droplets (see Fig. 2.6 ). The best understood example is the secretion of milk fat by mammary gland cells, where a small amount of cytoplasm is incorporated into the plasma membrane-bound lipid globule as it is released from the cell. Larger amounts of cytoplasm are included in secretions by specialized apocrine sweat glands in the axilla ( ) and anogenital regions of the body. A combination of different types of secretion occurs in some tissues, e.g. mammary gland cells secrete milk fat by apocrine secretion and milk protein, casein, by merocrine secretion.
In holocrine glands, the cells first fill with secretory products after which the entire cell disintegrates to liberate the accumulated mass of secretion into the adjacent duct or, more usually, hair follicle, e.g. sebaceous glands in the skin (see Fig. 2.6 ).
Structural and functional classification
Exocrine glands may be unicellular or multicellular. The latter may be in the form of simple sheets of secretory cells, e.g. the lining of the stomach, or may be structurally more complex and invaginated to a variable degree. Such glands may be simple units or their connection to the surface may be branched (see Fig. 2.6 ). Simple unbranched tubular glands exist in the walls of many of the hollow viscera, e.g. the small intestine and uterus, whereas some simple glands have expanded, flask-like ends (acini or alveoli). Such glands may consist entirely of secretory cells, or may have a blind-ending secretory portion that leads through a non-secretory duct to the surface, in which case the ducts may modify the secretions as they pass along them.
Glands with ducts may be branched (compound) and sometimes form elaborate ductal trees. Such glands generally have acinar or alveolar secretory lobules, as in the exocrine pancreas, but the secretory units may alternatively be tubular or mixed tubulo-acinar. More than one type of secretory cell may occur within a particular secretory unit, or individual units may be specialized to just one type of secretion (e.g. serous acini of salivary glands).
Exocrine glands are also classified by their secretory products. Secretory cells in mucus-secreting or mucous glands have frothy cytoplasm and basal, flattened nuclei. They stain deeply with metachromatic stains and periodic acid–Schiff (PAS) methods that detect carbohydrate residues. However, in general (i.e. non-specific) histological preparations, they are weakly stained because much of their content of water-rich mucin has been extracted by the processing procedures. Secretory cells in serous glands have centrally placed nuclei and eosinophilic secretory storage granules in their cytoplasm. They secrete mainly glycoproteins (including lysozyme) and digestive enzymes.
Some glands are almost entirely mucous (e.g. the sublingual salivary gland), whereas others are mainly serous (e.g. the parotid salivary gland). The submandibular gland is mixed, in that some lobules are predominantly mucous and others serous. Mucous acini may share a lumen with clusters of serous cells (seen in routine preparations as serous demilunes). Although this simple approach to classification is useful for general descriptive purposes, the diversity of molecules synthesized and secreted by glands is such that complex mixtures often exist within the same cell.
Endocrine glands
Endocrine glands secrete directly into connective tissue interstitial fluid and thence the circulation. Their cells are grouped around beds of capillaries or sinusoids, typically lined by fenestrated endothelia to allow the rapid passage of macromolecules through their walls. Endocrine cells may be arranged in clusters within vascular networks, in cords between parallel vascular channels or as hollow structures (follicles) surrounding their stored secretions. In addition to the cells of specialized ductless endocrine glands (e.g. pituitary, pineal, thyroid and parathyroid), hormone-producing cells also form components of other organ systems. These include the cells of the pancreatic islets; thymic epithelial cells; renin-secreting cells of the kidney juxtaglomerular apparatus; erythropoietin-secreting cells of the kidney; cells of the circumventricular organs; interstitial testicular (Leydig) cells; interstitial follicular and luteal ovarian cells; and placental cells (in pregnancy). Some cardiac myocytes, particularly in the walls of the atria, also have endocrine functions. These cells are all described in detail within the appropriate regional sections.
Isolated endocrine cells scattered amongst other tissues form part of the dispersed neuroendocrine system, e.g. throughout the alimentary and respiratory tracts. They produce peptide hormones, many of which may function as neurotransmitters: they can express neurone-specific enolase, synaptophysin, secretogranins and chromogranins as well as enzymes involved in peptide hormone synthesis and processing ( ). Neuroendocrine cells are generally situated within a mucosal epithelium and their bases often rest on the basal lamina. In response to an external stimulus, they secrete their product basally into interstitial fluid. They typically have a well-developed rough endoplasmic reticulum for peptide synthesis, large Golgi complexes for packaging their hormones, and numerous secretory granules that store and also transport the hormones to the cell surface for release by exocytosis ( Fig. 2.7 ). The secretory granules vary in shape, size and ultrastructure according to cell type. Neuroendocrine cells often take the name of the secretion they produce, e.g. gastrin-secreting G cells of the small intestine.
Control of glandular secretion
The activities of cells in the various tissue and organ systems of the body are tightly regulated by the coordinated activity of the endocrine and autonomic nervous systems. Endocrine (and paracrine) signals reach target cells in interstitial fluid, often via blood plasma, and together with autonomic nervous signals they ensure that the body responds to normal physiological stimuli and adjusts to changes in the external environment. Hormone secretion is itself controlled in a number of ways, e.g. by neural control, regulatory feedback loops or according to various cyclical, rhythmical or pulsatile patterns of release. Endocrine glands have a rich vascular supply and their blood flow is controlled by autonomic vasomotor nerves, which can thus modify glandular activity.
Glandular activity may also be controlled directly by autonomic secretomotor fibres, which may either form synapses on the bases of gland cells (e.g. in the suprarenal medulla) or release neuromediators in the vicinity of the glands and reach them by diffusion. Alternatively, the autonomic nervous system may act indirectly on gland cells, e.g. on neuroendocrine G cells via histamine, released neurogenically from another neuroendocrine cell in the gastric lining. Such paracrine activities of neuroendocrine cells are also important in the respiratory system.
Circulating hormones from the adenohypophysis stimulate synthesis and secretion by target cells in many endocrine glands. Such signals, mostly detected by receptors at the cell surface and mediated by second messenger systems, may increase the synthetic activity of gland cells, and may cause them to discharge their secretions by exocytosis. Secretions from certain exocrine glandular cells are expressed rapidly from those glands by the contraction of associated myoepithelial cells (see Figs 2.3 – 2.4 ) that enclose the secretory units and smaller ducts. Myoepithelial cells may be under direct neural control, as in the salivary glands, or they may respond to circulating hormones, as in the mammary gland, where they respond to the concentration of circulating oxytocin.
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