Unit 02 — Epithelial Tissue · Question Bank

Covering epithelia are the body's interfaces — every surface that contacts the outside world or an internal lumen is faced with epithelium, and the geometry of that epithelium is tuned to the job it must do. The examiner here is testing whether you can read an epithelium structurally and predict its function, so the classification is not a memory list but a two-axis grid built from how many layers the epithelium has and what shape its surface cells take.

Why two axes

The layer count tells you about protection: a single layer (simple) is thin and good for exchange or secretion; multiple layers (stratified) are thick and protective, sacrificing the surface cells to abrasion while basal cells divide to replace them. The cell shape tells you about metabolic activity: flat (squamous) cells are minimal cytoplasm wrapped around a flat nucleus — the thinnest possible barrier — while tall (columnar) cells have room for the rough ER, Golgi and secretory vesicles needed for active absorption or secretion. Reading both axes together lets you predict, from a single field of view, what an unknown epithelium probably does.

Simple epithelia — thinness for exchange

A single layer is the right design wherever something must cross the epithelium rather than be kept out by it. The flatter the cells, the shorter the diffusion path.

• Simple squamous — a single layer of plate-like cells. Lines the alveoli of the lung, where the entire blood–gas barrier is just two squamous cells (alveolar pneumocyte + capillary endothelium) thick — oxygen and CO₂ have to diffuse across in milliseconds, so anything thicker would suffocate the animal. The same logic gives endothelium in blood vessels and mesothelium in the pleura, pericardium and peritoneum.
• Simple cuboidal — cube-shaped cells with a central round nucleus. Lines the thyroid follicles (where the cells must synthesise and store thyroglobulin) and renal tubules (where they actively transport ions). Cuboidal shape is the compromise between thinness and the metabolic machinery the cell needs.
• Simple columnar — one row of tall cells with basal oval nuclei. Lines the stomach (mucus-secreting surface cells) and the small and large intestine, where the apical surface bears microvilli for absorption and goblet cells for mucus — the height gives room for the secretory and absorptive machinery.

Pseudostratified columnar — one layer that looks like many

Every cell still touches the basement membrane, but not every cell reaches the lumen, so the nuclei sit at different heights and the epithelium appears stratified. It is functionally simple. The ciliated form with goblet cells lines the trachea and bronchi — the mucociliary escalator. The stereociliated form lines the epididymis, where long branched microvilli absorb residual testicular fluid.

Stratified epithelia — layers for protection

Where the surface is abraded, dried out or chemically attacked, the epithelium piles up cells so that loss of the surface row does not breach the barrier. Stratified epithelia are named by the shape of their surface cells, not the basal ones.

• Stratified squamous keratinised — surface cells die, lose their nuclei and fill with keratin to form a dry waterproof crust. This is the epidermis, and the keratin is the reason you do not desiccate in air.
• Stratified squamous non-keratinised — surface cells stay flat but nucleated and moist; found in oesophagus, mouth, vagina and cornea, all of which sit in a wet lumen and need abrasion resistance without waterproofing.
• Stratified cuboidal — two or three layers of cube-shaped cells lining the larger excretory ducts of sweat glands, giving a tougher duct wall than a simple epithelium.
• Stratified columnar — rare; surface row of columnar cells over polygonal basal cells in the conjunctiva, parts of male urethra and large gland ducts.

Transitional epithelium (urothelium) — built to stretch

The urinary tract has a unique problem: its lining must distend without tearing as the bladder fills and must resist urine, which is hypertonic and cytotoxic. Urothelium solves both. When empty, the surface umbrella cells dome into the lumen and the epithelium looks 5–6 layers thick; when distended they flatten and the epithelium thins to 2–3 layers. The apical membrane of the umbrella cell is reinforced by rigid plaques of uroplakin that act as a urine-proof seal. Lines the renal calyces, ureter, urinary bladder and upper urethra.

Clinical link

The clinical importance of getting the classification right is that epithelial cancers are named for the epithelium they arise from: squamous-cell carcinoma in stratified squamous epithelia (skin, oesophagus, cervix), adenocarcinoma in glandular simple columnar epithelium (stomach, colon, lung adenocarcinoma from bronchial gland cells), and urothelial (transitional-cell) carcinoma in the bladder. The histological diagnosis — and therefore the staging and treatment — rests on first recognising the parent epithelium.

The free surface of an epithelial cell is the apical face that points into a lumen — air in the bronchi, chyme in the gut, urine in the bladder, sound waves in the cochlea. A flat plasma membrane would be wasteful here: an epithelium that has to absorb, propel or sense the lumen needs to amplify its apical area or place machinery on it. Evolution has produced three distinct apical specialisations — microvilli, cilia and stereocilia — each with a different cytoskeletal core that determines what it can do.

Microvilli — multiplying surface area for absorption

Microvilli are short (~1 µm), uniform finger-like projections of the apical membrane and cytoplasm, each supported by a parallel bundle of actin filaments cross-linked by villin and fimbrin and anchored basally into the terminal web. Because actin filaments are static here (no associated motor), microvilli are non-motile — their job is purely geometric. A dense lawn of microvilli on an intestinal enterocyte multiplies its absorptive area roughly 20-fold, which is why the absorptive small-intestine surface area is measured in tens of square metres in a tube only a few metres long.

On the light microscope this dense apical fringe appears as the striated border of intestinal enterocytes and the brush border of proximal convoluted tubule cells — the same structure under two historical names, present wherever bulk solute and water uptake is the cell's main job. The glycocalyx coating the microvilli also anchors the brush-border digestive enzymes (lactase, sucrase-isomaltase, peptidases) so that final hydrolysis happens immediately next to the absorbing membrane.

Cilia — moving the luminal contents

Cilia are longer (~5–10 µm) motile projections built around an entirely different cytoskeletal core called the axoneme: nine peripheral microtubule doublets arranged around a central pair of singlets — the 9 + 2 pattern — anchored basally to a basal body (a modified centriole). The motor protein is dynein: dynein arms walk one doublet against its neighbour, and because the doublets are tethered by nexin links, this sliding is converted into a coordinated bending beat. Adjacent cells beat in metachronal waves so that the luminal contents move in one direction.

This is why ciliated pseudostratified epithelium lines the entire tracheobronchial tree: goblet cells lay down a sticky mucus blanket that traps inhaled particles, and the cilia sweep that blanket up to the pharynx (the mucociliary escalator) where it is swallowed. The same machinery in the uterine tube wafts the ovum toward the uterus, and in the ependyma of the brain ventricles helps circulate CSF.

When ciliary dynein is defective — primary ciliary dyskinesia / Kartagener syndrome — the escalator fails: patients suffer recurrent sinusitis and bronchiectasis (mucus is not cleared), male infertility (sperm flagella share the 9+2 axoneme and cannot beat) and situs inversus (embryonic node cilia, which establish left–right asymmetry, also fail). In cystic fibrosis the cilia are normal but the mucus they must move is dehydrated and viscous because the apical CFTR chloride channel is broken — same clinical end (bronchiectasis) by a different mechanism.

Stereocilia — misnamed giant microvilli

Stereocilia look hair-like, but they are not cilia at all — they are very long, often branched microvilli with an actin core, non-motile. They line the epididymis and ductus deferens, where they absorb residual testicular fluid and contribute to sperm maturation, and they form the mechanosensory bundles on the hair cells of the inner ear: graded deflection of the stereocilia opens cation channels and converts mechanical sound or head-motion into receptor potentials. The name predates the electron microscope — keep them firmly in the actin/microvillus family.

Glycocalyx and terminal web — the supporting cast

The apical membrane is coated by a carbohydrate-rich glycocalyx of membrane-anchored glycoproteins and glycolipids that protects the surface from acid and enzymes (especially important in the gut), holds the brush-border hydrolases in place and mediates cell–cell and cell–pathogen recognition. Just beneath the apical membrane the terminal web — a meshwork of actin and spectrin filaments — anchors the microvillus rootlets, stiffens the apex against the pressure of luminal contents, and links to the zonula adherens belt that runs around the cell.

Clinical link

The three specialisations together illustrate how a single rule — matching cytoskeletal core to apical function — explains both normal physiology and an entire family of diseases: microvillus loss in coeliac disease blunts absorption and causes diarrhoea; ciliary defects in Kartagener and CF cripple airway clearance; stereocilia damage from aminoglycosides or noise causes sensorineural deafness.

An epithelium has to solve two problems at once. It must seal the lumen off from the underlying tissue — otherwise gut bacteria, urine or inhaled particles would leak straight into the body — and it must hold its own cells together against the mechanical stresses of stretching, abrasion and shear. A single junction cannot do both. Instead, every epithelial cell carries a stack of different junctions arranged in a fixed order from apical to basal, each built from its own family of transmembrane proteins, each linked to its own cytoskeletal partner. This stack is the junctional complex.

What “junctional complex” means

Farquhar and Palade in 1963 defined the junctional complex as the apex-to-base aggregation of three junctions seen consistently together on the lateral surface of every simple epithelium: the zonula occludens (tight junction) at the top, the zonula adherens just below it, and one or more maculae adherentes (desmosomes) deeper still. Gap junctions appear alongside these as communicating channels, and hemidesmosomes anchor the cell to the basement membrane at its base. Reading the complex top-down lets you predict which protein, and therefore which disease, sits at each level.

Zonula occludens (tight junction) — the seal

The most apical element. Transmembrane claudin and occludin proteins in one cell line up with their partners in the next cell and effectively fuse the outer leaflets of the two membranes along ridges that run as a continuous belt around the cell. The result is a paracellular barrier: molecules cannot squeeze between the cells, they must go through them, which lets the epithelium control what crosses. The same belt also acts as a diffusion fence on the membrane itself, stopping apical membrane proteins from drifting laterally into the basolateral domain and vice versa — this is how epithelial polarity is maintained. Different claudin isoforms make the barrier “tighter” or “leakier” in different organs, which is why the proximal tubule is leaky (claudin-2 allows paracellular Na⁺/water reabsorption) while the distal nephron is tight.

Zonula adherens (intermediate junction) — the contractile belt

Sits immediately deep to the tight junction. Adjacent membranes are separated by a narrow uniform gap that is spanned by E-cadherin, a calcium-dependent homophilic adhesion molecule. The cytoplasmic tail of E-cadherin binds α- and β-catenin, and the catenins anchor into a circumferential band of actin filaments running just inside the membrane. The two belts together form a contractile ring shared around the apex of every cell — this is what drives epithelial folding during gastrulation and neurulation. Loss of E-cadherin is a hallmark of epithelial-to-mesenchymal transition in invasive carcinomas; diffuse-type gastric cancer and lobular breast cancer both classically lose E-cadherin and infiltrate as scattered single cells (signet rings) rather than as a cohesive mass.

Macula adherens (desmosome) — the spot-weld

Below the zonula adherens, junctions become discontinuous — spot-like “rivets” rather than belts. Each desmosome has a dense cytoplasmic plaque of desmoplakin and plakoglobin on each cell; transmembrane desmoglein and desmocollin (cadherin-family) molecules cross the intercellular space and clip onto their partners on the next cell. Crucially, keratin intermediate filaments insert into the plaque from inside — so the desmosomes of all the cells of an epithelium are linked into a single tissue-wide network of keratin cables that distributes mechanical stress. This is why desmosomes are densest in epithelia under shear: the epidermis, the cervix, the oesophagus.

When IgG autoantibodies attack desmoglein-3 the desmosomes between basal keratinocytes fall apart and the cells separate (acantholysis): this is pemphigus vulgaris, which presents with painful flaccid bullae and oral erosions, positive Nikolsky sign. By contrast bullous pemphigoid is caused by antibodies against the hemidesmosome protein BP180/BP230, so the split is between epidermis and dermis — deeper, tense, less painful blisters. Same family of disease, different junction targeted, different clinical picture.

Gap junction (nexus) — the communicating channel

Six connexin subunits in one cell assemble into a connexon hemichannel; aligned hemichannels in adjacent cells form an open aqueous pore that lets ions and small molecules (<1 kDa) pass cytoplasm-to-cytoplasm. The cells are now electrically and metabolically coupled, which is essential wherever a tissue must act as a syncytium: cardiac muscle (intercalated discs carry gap junctions so the action potential propagates from cell to cell), smooth muscle of the gut, follicular cells of the ovary, osteocytes through their canalicular processes. Connexin mutations cause hereditary deafness (connexin-26) and Charcot–Marie–Tooth X-linked neuropathy (connexin-32).

Hemidesmosome — anchoring to the basement membrane

At the base of the cell, “half”-a-desmosome appears: a single cytoplasmic plaque, with integrin α₆β₄ as the transmembrane molecule reaching down into the basal lamina and binding to laminin-332. Keratin filaments insert into the plaque from inside, completing the chain that links the keratin cytoskeleton of the epithelium to the type IV collagen scaffold of the basement membrane. Genetic disruption of any link in this chain causes the epidermolysis bullosa family of blistering diseases.

Clinical link

The whole complex can be read as a vertical map of skin and mucous disease: pemphigus splits at the desmoglein-3 level (suprabasal blisters), pemphigoid splits at the BP180/integrin-β₄ level (subepidermal blisters), and epidermolysis bullosa simplex hits the keratin filaments that anchor into the desmosomes. Naming the junction localises the lesion in the cell and explains the depth of the blister on biopsy.

The basement membrane is the interface between two utterly different tissue worlds — the cellular, avascular sheet of epithelium above and the fibroblast-rich, vascular connective tissue below — and almost everything that travels in either direction has to cross it. It is simultaneously a glue (anchoring epithelium to CT), a barrier (keeping molecules and cells where they belong) and a filter (in the kidney, the principal sieve of plasma). Reading its structure layer by layer explains all of these functions.

Where it is found

A basement membrane sits at every epithelial–connective-tissue interface in the body. It also wraps around individual muscle fibres, Schwann cells, adipocytes and the capillary endothelium — anywhere a non-CT cell needs to be cordoned off from the surrounding stroma. In the glomerulus a particularly thick, modified basement membrane is sandwiched between podocyte and endothelial cell as the central sheet of the filtration barrier.

Light-microscopic appearance

On routine H&E it shows only as a faint, often unresolved pink line under the epithelium — too thin and too uniform to stand out. Two histochemical stains bring it out dramatically because they target its main chemical constituents: PAS turns it magenta because it is rich in carbohydrate (the heavily glycosylated type IV collagen, laminin and proteoglycans), and silver impregnation turns it black because of the reticular fibres of the deep layer. Both stains are routinely used in renal biopsy to assess GBM thickness and integrity.

Electron-microscopic architecture

Under EM the basement membrane resolves into a superficial basal lamina (50–100 nm, produced by the epithelium) and a deeper reticular lamina (produced by the connective tissue fibroblasts). The basal lamina is itself stratified into two sublayers, and each molecular component does a specific mechanical or filtration job.

• Lamina lucida (electron-lucent, immediately beneath the epithelium) — mainly laminin molecules projecting down from the epithelial cell, with integrins of the hemidesmosomes reaching into it. This is the molecular handshake that grips the cell to the sheet.
• Lamina densa (electron-dense) — a felt-like meshwork of type IV collagen (a network-forming, non-fibrillar collagen built from α1–α6 chains that polymerise into a chicken-wire lattice), with laminin, perlecan (a heparan sulfate proteoglycan whose negative charges contribute to the charge barrier in the glomerulus) and nidogen/entactin (which clips laminin to type IV collagen and holds the lattice together). Type IV collagen provides the tensile scaffold; laminin organises the cells on it; perlecan provides the negative-charge sieve.
• Reticular lamina — produced by CT fibroblasts. A layer of reticular fibres (type III collagen) anchored to the lamina densa by anchoring fibrils of type VII collagen that loop down into the connective tissue and trap matrix in the loop. Defects in type VII collagen produce dystrophic epidermolysis bullosa, in which the entire epidermis shears off the dermis.

Functions read off the architecture

• Structural attachment — the integrin–laminin–type IV–type VII chain from the hemidesmosome down into the CT physically clips epithelium to stroma. Break any link and the epithelium sloughs (the epidermolysis bullosa family).
• Selective filter — in the glomerulus the lamina densa is the principal filtration barrier: type IV collagen sets the size cut-off, and the heparan sulfate of perlecan sets the negative-charge cut-off that repels albumin. Loss of charge selectivity (minimal-change disease) produces selective albuminuria; loss of size selectivity (membranous nephropathy) produces non-selective proteinuria.
• Scaffold for repair — after epithelial injury, migrating epithelial cells use the surviving basement membrane as a track to re-cover the wound and re-establish polarity. If the basement membrane is destroyed (full-thickness burn, chronic ulcer) the repair is disordered and scars instead of regenerating.
• Compartmentalisation and invasion barrier — the basement membrane separates epithelium from CT and from blood vessels. Penetration of the basement membrane is the histological definition of invasive carcinoma (in situ carcinoma still respects the membrane; invasive carcinoma has broken it down using matrix metalloproteinases). Loss of basement-membrane integrity therefore changes both stage and prognosis.

Clinical link

Two diseases illustrate the role of type IV collagen better than any diagram. Goodpasture syndrome is caused by IgG autoantibodies against the non-collagenous (NC1) domain of the α₃ chain of type IV collagen; because this chain is present in both the glomerular and the alveolar basement membranes, patients present with the diagnostic dyad of rapidly progressive crescentic glomerulonephritis and pulmonary haemorrhage. Alport syndrome is the mirror image — an X-linked mutation in the α₅ chain of type IV collagen — producing a structurally faulty GBM that splits and laminates on EM, leading to haematuria, progressive renal failure, sensorineural deafness and lens defects (the same chain is in cochlear and ocular basement membranes). Diabetic nephropathy shows non-enzymatic glycation thickening the GBM and trapping albumin, the structural correlate of the microalbuminuria seen clinically.

A gland is not a tissue in its own right — it is epithelium that has dived into the underlying connective tissue and specialised for secretion. The way it disposes of its product splits all glands into two great families, and within the exocrine family the way the cell releases its secretion gives rise to three quite different mechanisms with very different clinical signatures. The examiner is testing whether you can walk the classification top-down and anchor each branch to a real organ.

Endocrine vs exocrine — a developmental story

During embryonic development a bud of surface epithelium grows down into the mesenchyme. If the connecting stalk persists as a hollow duct that delivers secretion back to an epithelial surface, the gland is exocrine — salivary glands onto the mouth, sweat glands onto skin, pancreas onto the duodenum. If the stalk degenerates and the deep cells instead release their product into the surrounding capillary plexus, the gland is endocrine — thyroid, adrenal, pituitary, pancreatic islets. This is why every endocrine organ has an unusually rich, fenestrated capillary bed: hormones must reach the bloodstream within seconds.

Classifying exocrine glands — four independent axes

Once you know a gland is exocrine, it is described along four orthogonal axes, each of which gives the histologist independent diagnostic information.

• By number of cells — unicellular exocrine glands are a single goblet cell scattered among absorptive cells (in the intestinal and respiratory epithelium), secreting mucinogen directly onto the surface. Multicellular glands are everything else.
• By duct branching — if the duct is unbranched the gland is simple (e.g. eccrine sweat); if the duct system branches the gland is compound (e.g. submandibular, parotid, pancreas).
• By shape of secretory unit — cells may be arranged as a tubule (intestinal crypts), a rounded acinus/alveolus (parotid), or a tubuloacinar mix (submandibular). The shape is set by the volume of secretion the unit must store.
• By nature of secretion — the cytology immediately distinguishes the two: serous cells are small, with intensely basophilic basal cytoplasm (packed rough ER for protein synthesis), a round basal nucleus and apical eosinophilic zymogen granules — they make a watery, enzyme-rich fluid (parotid, pancreas). Mucous cells are pale and bloated, their nucleus pushed and flattened against the base by a column of pale mucinogen (goblet cells, sublingual gland). In mixed/seromucous glands such as the submandibular, mucous tubules are capped by crescentic serous demilunes whose serous fluid reaches the lumen by squeezing between the mucous cells through intercellular canaliculi.

Modes of exocrine secretion — how much of the cell goes with the product

The three release mechanisms differ in exactly that: how much of the cell is sacrificed when the secretion leaves.

• Merocrine (eccrine) — default exocytosis, no cell loss. Secretory vesicles fuse with the apical membrane, dump their contents into the lumen, and the cell is left intact and ready to refill. This is the mechanism used by the overwhelming majority of glands — pancreatic acini releasing zymogens, salivary serous cells releasing α-amylase, and the eccrine sweat glands distributed over almost the entire body. The clinical anchor here is cystic fibrosis: sweat is initially isotonic, then NaCl is reabsorbed as it travels up the duct by apical CFTR-driven Cl⁻ reabsorption. In CF the CFTR channel is broken, Cl⁻ cannot be reclaimed, sweat reaches the skin with abnormally high NaCl — this is the basis of the diagnostic sweat chloride test.
• Apocrine — apical cytoplasm pinched off with the product. A thin rim of cytoplasm and a piece of apical membrane are shed together with the secretion. The classic and clinically important example is the lactating mammary gland: lipid droplets accumulate at the apex of the alveolar cell and are pinched off with a membrane envelope of cytoplasm (the milk-fat globule membrane), giving breast milk its characteristic fat globules. Interestingly, the protein component of milk in the same cell is released by ordinary merocrine exocytosis — a single cell using two modes for two products. The axillary “apocrine sweat glands” were named on EM appearance but are now thought to release most of their product merocrine-style; their secretion only becomes the odour we associate with body smell after skin bacteria metabolise it.
• Holocrine — the cell is the product. The entire secretory cell fills up with product, dies, and disintegrates into the lumen; new cells continuously divide at the periphery to replace those sacrificed at the centre. The textbook example is the sebaceous gland of the skin: sebocytes at the basal layer divide, migrate centrally, accumulate lipid until they burst, and the cell debris and lipid together constitute sebum, which is delivered into the hair follicle. The clinical anchor is acne vulgaris: under androgenic stimulation at puberty sebum output rises, the follicular opening keratinises shut, sebum and shed corneocytes form a comedone, Cutibacterium acnes proliferates in the trapped lipid and triggers neutrophilic inflammation — the papules and pustules of acne are the downstream consequence of a holocrine gland running at full speed.

Myoepithelial cells — the contractile basket

Sitting between the secretory cells and the basal lamina of salivary, mammary and sweat acini are myoepithelial cells — epithelial in origin but stuffed with actin and myosin, with long basket-like processes that wrap each acinus. They contract on demand and squeeze stored secretion into the duct. In the lactating breast, oxytocin released by suckling drives myoepithelial contraction to give the milk-ejection reflex; in salivary and sweat glands autonomic input does the same job.

Clinical link

The three secretory modes together give a complete answer to “why does the same skin make oily sebum, watery sweat and milky lipid in different places?” — the cell uses three different release strategies for three different physical products, and disease arises when any of the three goes wrong: CF in eccrine sweat, mastitis when apocrine ducts block, acne when holocrine sebum cannot escape.