Chapter 4: Epithelial and Connective Tissue


I. Overview

The human body comprises a diverse assemblage of cells that can be placed in one of four groups based on structural and functional similarities. These groups are known as tissues: epithelial tissue, nervous tissue, muscle tissue, and connective tissue. The four tissue types associate with and work in close cooperation with each other. Epithelial tissue comprises sheets of cells that provide barriers between the internal and external environment. Skin (the epidermis) is the most visible example (see Chapter 16), but there are many unseen internal interfaces that are lined with epithelia also (e.g., lungs, gastrointestinal [GI] tract, kidneys, and reproductive organs).

Nervous tissue comprises neurons and their support cells (glia) that provide pathways for communication and coordinate tissue function, as will be discussed in greater detail in Unit II. Muscle tissue is specialized for contraction. There are three types of muscle: skeletal muscle (see Chapter 12), cardiac muscle (see Chapter 13), and smooth muscle (see Chapter 14). Connective tissue is a mix of cells, structural fibers, and ground substance that connects and fills the spaces between adjacent cells and gives tissues their strength and form. Bone is a specialized connective tissue that is mineralized to provide strength and to resist compression (see Chapter 15). This chapter considers the structure and varied functions of epithelial tissue (Table 4.1) and connective tissue.

Table 4.1: Epithelial Functions

Function Examples
Protection Epidermis; mouth; esophagus; larynx; vagina; anal canal
Excretion Kidney
Secretion Intestine; kidney; most glands
Absorption Intestine; kidney
Lubrication Intestine; airways; reproductive tracts
Cleansing Trachea; auditory canal
Sensory Gustatory, olfactory, and vestibular epithelia
Reproduction Germinal, uterine, and ovarian epithelia

II. Epithelia

Epithelia are continuous sheets of cells that line all body surfaces and create barriers that separate the internal and external environments. They help protect us from invasion by microorganisms, and they limit fluid loss from the internal environment: They “keep our insides in.” Epithelia are much more than just barriers, however. Most epithelia have additional specialized secretory or absorptive functions that include sweat formation, food digestion and absorption, and excretion of waste products.

A. Structure

The simplest epithelia comprise a single layer of cells adhered to each other by a variety of junctional complexes that impart mechanical strength and create pathways for communication between adjacent cells (Figure 4.1). The apical surface interfaces with the external environment (or an internal body cavity), whereas the basal surface rests on a basement membrane that provides structural support.

The basement membrane comprises two fused layers. The basal lamina is synthesized by the epithelial cells that it supports and is composed of collagen and associated proteins. The inner layer (lamina reticularis, or reticular lamina) is formed by underlying connective tissue. Epithelia are avascular, relying on blood vessels lying close to the basement membrane to deliver O2 and nutrients, but they are innervated.

Figure 4.1 Epithelial cell structure.

B. Types

Epithelia are classified based on their morphology, which is usually a reflection of their function. There are three types: simple epithelia, stratified epithelia, and glandular epithelia.

1. Simple

Many epithelia are specialized to facilitate exchange of materials between their apical surface and the vasculature. For example, the pulmonary epithelium facilitates gas exchange between the atmosphere and the pulmonary circulation (see 22?II?C). The renal tubule epithelium transfers fluid between the tubule lumen and blood (see 26?II?C), whereas the epithelium that lines the small intestine transfers materials between the intestinal lumen and the circulation (see 31?II). Exchange and transport functions require that the barrier separating the two compartments be minimal, so all of the above structures are lined with “simple” epithelia.

Simple epithelia comprise a single cell layer and can be further subdivided into three groups according to epithelial cell shape. Pulmonary alveoli and blood vessels are lined with simple squamous epithelium. Squamous epithelial cells are extremely thin to maximize diffusional exchange of gases. Many segments of renal tubules and glandular ducts are lined with cube-shaped (simple cuboidal) epithelial cells.

Their shape reflects the fact that they actively transport materials and, thus, they must accommodate mitochondria to produce the adenosine triphosphate (ATP) needed to support primary active transporter function. Simple columnar epithelia comprise sheets of cells that are long and narrow to accommodate large numbers of mitochondria and are found in the distal regions of the renal tubule (see 27?IV?A) and in the intestines, for example.

Clinical Application 4.1: Squamous Cell Carcinoma

Squamous cell carcinomas are one of the most common forms of cancer that arise from most epithelia, including the skin, lips, buccal lining, esophagus, lungs, prostate, vagina, cervix, and urinary bladder. Cutaneous squamous cell carcinoma is a prevalent skin cancer that typically occurs in sun-exposed skin areas. Squamous cell malignancies are believed to arise from uncontrolled division of epithelial stem cells rather than squamous epithelial cells. Squamous cell cancers usually remain localized and can be treated by Mohs surgery (a specialized dermatologic surgery for skin malignancies), cryotherapy, or surgical excision

Squamous cell carcinoma.

Photograph from Berg, D. and Worzala, K. Atlas of Adult Physical Diagnosis. Lippincott Williams & Wilkins, 2006.

2. Stratified

Epithelia that are subject to mechanical abrasion are composed of multiple cell layers (Figure 4.2). The layers are designed to be sacrificed to prevent exposure of the basement membrane and deeper structures. The inner epithelial cell layers are renewed continually and the damaged outer layers sloughed off. Examples include the skin and the lining of the mouth, esophagus, and vagina. The skin suffers constant exposure to mechanical stress associated with contact with and manipulation of external objects, so the outer layers are reinforced with keratin, a resilient structural protein (see 16?III?A).

Transitional epithelium (also known as urothelium) is a specialized stratified epithelium that lines the urinary bladder, ureters, and urethra (see 25?VI). A transitional epithelium comprises cells that readily stretch and change shape (from cuboidal to squamous) without tearing to accommodate volume changes within the structures that they line.

Figure 4.2 Stratified epithelial structure.

3. Glandular

Glandular epithelia produce specialized proteinaceous secretions (Figure 4.3). Glands are formed from columns or tubes of surface epithelial cells that invade the underlying structures to form invaginations. Glandular secretions are then released either via a duct or ductal system onto the epithelial surface (exocrine glands), or across the basement membrane into the bloodstream (endocrine glands). Endocrine glands include the adrenal glands (which secrete epinephrine), the endocrine pancreas (which secretes insulin and glucagon), and reproductive glands, which are considered in Unit VIII. Sweat glands, salivary glands, and mammary glands are all examples of exocrine glands. Exocrine glands are typically composed of two epithelial cell types: serous and mucous.

Figure 4.3 Glandular epithelial structure.

a. Serous

Serous cells produce a watery secretion containing proteins, typically enzymes. Salivary serous cells produce salivary amylase, gastric chief cells produce pepsinogen (a pepsin precursor) and pancreatic exocrine serous cells produce trypsinogen, chymotrypsinogen, pancreatic lipase, and pancreatic amylase.

b. Mucous

Mucous cells secrete mucus, a slippery glycoprotein (mucin)-rich secretion that lubricates the surface of mucous membranes. Many glands contain a mix of serous and mucous cells that together create an epithelial barrier layer enriched with antibacterial agents such as lactoferrin to help ward off infection (e.g., pancreatic glands) or enriched with HCO3? to neutralize acid (e.g., gastric epithelium).

C. Apical specializations

Several epithelia support apical modifications that amplify surface area or serve motile or sensory functions, including villi, cilia (motile and sensory), and stereocilia (Figure 4.4).

Figure 4.4 Apical surface specializations.

From Mills, S.E. Histology for Pathologists. Third Edition. Lippincott Williams & Wilkins, 2007

1. Villi

Epithelia that are specialized for high-volume fluid uptake or secretion (e.g., epithelia lining the renal proximal tubule and small intestine) are folded extensively to create fingerlike projections (villi) that serve to amplify the surface area available for diffusion and transport (see Figure 4.4A). The epithelial cells that cover villi may also support microvilli, plasma-membrane projections that enhance surface area even further. Villi and microvilli are nonmotile.

2. Motile cilia

The epithelia that line the upper airways, brain ventricles, and fallopian tubes are covered with motile cilia. Cilia are hairlike organelles containing a 9 + 2 arrangement of microtubules that run the length of the organelle (Figure 4.5). Two microtubules are located centrally, and nine microtubule doublets run around the ciliary circumference. Adjacent microtubule doublets are associated with dynein (dynein arms are shown in Figure 4.5), which is a molecular motor (an ATPase). When activated, dynein causes adjacent microtubule doublets to slide against each other sequentially around the ciliary circumference, causing the cilium to bend or “beat.”

The synchronized beating of many thousands of cilia cause the mucus (e.g., in the airways; see 22?II?A) or cerebrospinal fluid ([CSF] see 6?VII?D) in which they are immersed to move over the epithelial surface (see Figure 4.4B). Respiratory cilia propel mucus and trapped dust, bacteria, and other inhaled particles upward and away from the blood–gas interface. In the brain, ciliary beating helps circulate CSF.

Figure 4.5 Microtubules within a motile cilium.

Modified from Chandar, N. and Viselli, S. Lippincott’s Illustrated Reviews: Cell and Molecular Biology. Lippincott Williams ; Wilkins, 2010

3. Sensory cilia

Epithelial cells lining the renal tubule each sprout a single central cilium that is nonmotile and is believed to monitor flow rates through the tubule. The olfactory epithelium also bears nonmotile cilia whose membranes are dense with odorant receptors (see 10?III?B).

4. Stereocilia

The sensory epithelium that forms the lining of the inner ear expresses mechanosensory stereocilia that transduce sound waves (organ of Corti; see 9?IV?A) and detect head motion (vestibular apparatus; see 9?V?A). Stereocilia are nonmotile epithelial projections more closely related to villi than to true cilia.

D. Basolateral membrane

The membranes of two adjacent epithelial cells come into close apposition just below the apical surface to form tight junctions (zona occludens) as shown in Figure 4.1. Tight junctions comprise continuous structural bands that link adjacent cells together, much as beverage cans are held together by plastic six-pack rings (Figure 4.6). Tight junctions effectively seal the apical surface of an epithelium and create a barrier, which, in some epithelia (e.g., distal segments of the renal tubule), is impermeant to water and solutes. Tight junctions also divide the epithelial plasma membrane into two distinct regions (apical and basal) by preventing lateral movement and mixing of membrane proteins.

The membrane located on the basal side of the tight junction includes the lateral and basal membranes, which are contiguous and together form a functional unit known as the basolateral membrane. The basolateral membrane usually contains a different complement of ion channels and transporters from the apical side (e.g., the Na+-K+ ATPase is usually restricted to the basolateral membrane) and may be folded to increase the surface area available for transporter proteins (e.g., some portions of the nephron). The basolateral membrane faces the vasculature across an interstitial space.

Figure 4.6 Model for an epithelium.

E. Tight junctions

Tight junctions contain numerous different proteins, the principal ones being occludin and claudin. Tight junctions serve several important functions: They form molecular “fences,” they determine tight-junction “leakiness,” and they regulate water and solute flow across epithelia.

1. Fences

Tight junctions prevent apical and basolateral membrane proteins from mixing (a fence function) and, thereby, allow epithelial cells to develop functional polarity (Figure 4.7). The apical membrane becomes specialized for moving material between the external environment and the cell interior, whereas the basolateral membrane moves material between the inside of the cell and the bloodstream (see below).

2. Leakiness

Adjacent cells within an epithelium are separated by a narrow space that creates a physical pathway for transepithelial fluid flow (the paracellular pathway). Tight junctions act as gates that limit paracellular fluid movement and, in so doing, define epithelial leakiness.

a. Leaky epithelia

The tight junctions in a “leaky” epithelium (e.g., renal proximal tubule; see 26?II) are highly permeable and allow solutes and water to pass with relative ease (see Figure 4.7). Leakiness prevents an epithelium from being able to create strong solute concentration gradients between external and internal surfaces, but leaky epithelia are capable of taking up large fluid volumes by paracellular flow.

Figure 4.7 Flow across a leaky epithelium.

ATP = adenosine triphosphate.

b. Tight epithelia

Tight junctions in “tight” epithelia effectively bar paracellular flow of water and solutes and allows an epithelium to become highly selective in what it absorbs or secretes (e.g., nephron distal segments; see 27?IV) as shown in Figure 4.8. An epithelium’s leakiness is defined by its electrical resistance. Because the tight junctions in tight epithelia restrict passage of ions, they have a high resistance to current flow (>50,000 Ohm), whereas leaky epithelia have low resistance (<10 Ohm).

Figure 4.8 Tight epithelia.

ATP = adenosine triphosphate.

Clinical Application 4.2: Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder characterized by an inability to reabsorb Mg2+ from the renal tubule. Plasma Mg2+ levels fall as a consequence (hypomagnesemia). The mutation also impairs Ca2+ reabsorption, which increases urinary excretion rates (hypercalciuria) and the likelihood of kidney stone formation (nephrocalcinosis).

Kidney stones form when urinary Ca2+ and Mg2+ concentrations are so high that their salts precipitate as crystals, which then aggregate and become lodged within the renal tubule (intrarenal calculi), ureters (ureteral calculi), or bladder. FHHNC is caused by claudin-16 gene mutations (the human genome contains 24 claudin genes). Claudin-16 forms a divalent cation-specific pathway (paracellin-1) for Mg2+ and Ca2+ reabsorption from the thick ascending limb of the loop of Henle. Mutations in claudin-19 can similarly produce renal Mg2+ wasting. Affected individuals typically require magnesium supplements and frequent lithotripsy to mechanically fragment kidney stones and allow them to pass out of the body.

Intrarenal calculi.

From Daffner, R.H. Clinical Radiology—The Essentials. Third Edition. Lippincott Williams & Wilkins, 2007

3. Regulation

Although tight junctions in leaky epithelia are highly permeable to water and solutes, they are selective about what they give passage to. Tight-junction permeability can also be regulated to increase or decrease net uptake of water and solutes via the paracellular route. For example, transcellular Na+-glucose transport by intestinal epithelia increases paracellular Na+-glucose transport through changes in tight-junction permeability. The mechanisms involved are not well delineated, but claudins clearly have a central role in determining the size and charge of permeant solutes, and myosin light-chain kinase is involved in regulating junctional permeability.

F. Gap junctions

Gap junctions are the location of gap-junction channels that provide pathways for communication between adjacent cells. They are found in many areas (including muscle and nervous tissue), but are so abundant in some epithelia (e.g., intestinal epithelia) that they are packed into dense crystalline arrays, each containing thousands of individual channels. Gap-junction channels are formed by the association of two connexin hemichannels (connexons) as shown in Figure 4.9.

Figure 4.9 Gap-junction channels.

1. Connexins

Gap-junction channels are formed by six connexin subunits that assemble around a central pore, and each subunit contains four membrane-spanning domains (see Figure 4.9). The human genome contains 21 connexin isoforms that yield channels with distinct gating properties, selectivities, and regulatory mechanisms when expressed. All 21 isoforms are associated with hereditary diseases, which underscores the significance of the gap-junction communication pathway.

Connexin gene mutations produce disorders ranging from idiopathic atrial fibrillation, congenital cataracts, hearing loss, and oculodentodigital dysplasia, to an X-linked form of Charcot-Marie-Tooth disease (CMT). CMT includes a diverse group of demyelinating disorders that primarily affect peripheral nerves, resulting in sensory loss, muscle wasting, and paralysis.

2. Connexons

A gap-junction channel forms when hemichannels from two adjacent cells contact each other end to end, align, and form a tight association (see Figure 4.9). Gap junctions, have a significant intercellular adhesion function also.

3. Gating

Gap-junction channels are gated by numerous factors, including the potential difference across the junction, membrane-potential changes, Ca2+, pH changes, and by phosphorylation. At rest, when the transjunctional potential is 0 mV, gap-junction channels are usually open.

4. Permeability

The gap-junction channel pore is sufficiently large to allow passage of ions, water, metabolites, second messengers, and even small proteins of up to around 1,000 MW. Gap junctions allow all cells within an epithelium to communicate with each other both electrically and chemically.

Clinical Application 4.3: Pemphigus Foliaceus

Pemphigus foliaceus is a rare autoimmune disorder that presents as scaly, crusting skin blisters located on the face and scalp, primarily, although the chest and back may become involved in later stages. Affected individuals express antibodies to desmoglein 1, an integral membrane protein that forms a part of the desmosomal complex. Symptoms typically are triggered by drugs (e.g., penicillin) and are caused by desmoglein 1 being targeted and degraded by the immune system. Adjacent skin epithelial cells become detached from one another, and the skin blisters. The blisters ultimately slough off and leave sores. Treatment includes immunosuppressive therapy.

Pemphigus foliaceus.