Learning Objectives

  • Describe how different types of epithelia (simple, stratified, squamous, columnar) facilitate the performance of different functions.
  • List the junctional complexes that hold epithelial cells together and their primary functions.
  • List the functions of the basement membrane and how epithelial cells attach to the basement membrane.
  • Diagram how proteins are targeted to the apical and basal surfaces.

Keywords

  • Simple epithelia
  • Squamous epithelia
  • Cuboidal epithelia
  • Columnar epithelia
  • Stratified epithelia
  • Cilia
  • Microvilli
  • Tight junctions
  • Adhering junctions
  • Desmosomes
  • Gap junctions
  • Integrins
  • Hemidesmosomes
  • Laminin
  • Type IV collagen
  • Fibronectin
  • Apical
  • Basal

Pre-Lecture Reading

Overview

Epithelia are a sheet of cells that covers most of the body surfaces, forms the functional unit of secretory glands and line the inner surface of blood vessels. Epithelia perform a wide variety of functions and adopt different cellular arrangements and structure to accomplish these functions. Epithelial cells are held together by tight junctions, adhering junction and desmosomes and attach to a specialized form of extracellular matrix called the basement membrane. Epithelial cells are polarized with an apical surface facing the lumen or external environment and a basal surface facing the basement membrane. The apical and basal surfaces have unique biochemical compositions.

Summary

  • Epithelial cells adopt of variety of structures from single layers of flattened or columnar cells to multiple layers of cells.
  • Epithelial cells are held together by tight junctions, adhering junctions and desmosomes.
  • Tight junctions regulate the paracellular transport of ions and small molecules and inhibit the mixing of proteins in the apical and basal membranes.
  • The secretory pathway sorts proteins to the apical and basal surfaces and uses transcytosis to transport material from the basal to apical surface.
  • Stem cells that replenish lost and damaged epithelial cells localize to different regions based on the type of epithelia.

Introduction

Epithelia are a sheet of cells that line almost all body surfaces (skin, intestine, lung, body cavities), form the functional units of secretory glands, and line the inner surface of blood and lymphatic vessels. Given the wide distribution, epithelial cells perform a variety of functions: protection (skin), absorption (intestine), secretion (glands), excretion (kidney), gas exchange (lung and blood vessels).

To perform these functions, epithelia assemble into different structures. Simple squamous epithelia are a single layer of flattened cells that because of their thinness, facilitate exchange of gases and are found in the lung and blood vessels. Simple cuboidal and columnar are taller and are actively involved in absorption and secretion. Both of these activities require more organelles for protein secretion (ER, Golgi) and/or energy generation (mitochondria), making these cells larger. Cuboidal and columnar cells are prominently found in intestine, glands and kidney. Stratified epithelia contain two or more layers of cells. Usually, the outer layer is squamous but in a few cases it is cuboidal or columnar. The multiple layers of cells in stratified epithelia provide better protection as they resist mechanical stress and dehydration. Skin contains stratified squamous epithelia.

Epithelia cells also contain additional structures that facilitate their activities. Epithelial cells involved in absorption often contain microvilli, finger-like projections of the plasma membrane, that increase the surface area of the plasma membrane, allowing for more efficient uptake of material. Some epithelial cells also contain cilia that are long, thin extensions of the plasma membrane. Cilia are motile and move in wave-like fashion to generate flow in a lumen. This allows epithelial cells to move directionally large particles: ovum in fallopian tubes, mucus in trachea.

Features of Epithelia

Epithelial cells are held together through a set of cell to cell interactions along their lateral surface: tight junctions, adhering junctions and desmosomes. Epithelial cells attach to a specialized kind of extracellular matrix called the basal lamina or basement membrane that separates epithelial cells from the underlying tissue. Epithelia cells are polarized with an apical surface that faces the lumen of a tube or the external environment and a basal surface that attaches to the basement membrane. The apical and basal surfaces perform different functions and have unique biochemical compositions. Epithelial cells are continuously renewed. Mechanical forces and harsh environmental conditions damage and kill cells. Every epithelium has a supply of stem cells to replenish lost or damaged cells.

Epithelial Cell Adhesion

Three sets of interactions tether epithelial cells. Adhering junctions and desmosomes were discussed in the Cell to Tissues lecture. The third complex is tight junctions. The position of these complexes along the lateral surface is ordered from apical to basal: tight junctions, adhering junctions and desmosomes.

Tight junctions perform a critical function besides cell adhesion. They restrict the diffusion of molecules between neighboring cells (paracellular). Tight junctions regulate the passage of ions and small metabolites, and the tightness of the diffusion barrier varies with the location of the epithelium: brain (tight), intestine (looser). In fact, the electrical resistance of some epithelia can differ by over 1000 fold.

Tight junctions are network of strands that encircle the cell and interact with similar strands on neighboring cells to form a seal around the cells. Tight junctions are linked intracellularly to actin filaments that stabilize the junctions.

There are over 40 proteins that make up a tight junction but claudins are thought to determine the diffusion properties of tight junctions. Claudins contain four transmembrane domains and interact with claudins in neighboring cells. Their intracellular domains interact with a complex of proteins that associate with actin filaments. The interactions between claudins is thought to create pores that are restrictive to objects as small as 4 angtroms The pores can also be charge-selective, restricting either cations or anions. There are 24 different claudin genes that show tissue-specific expression, and the type of claudin in an epithelium has been shown to determine the electrical resistance of the epithelium. The paracellular transport of larger molecules (sugars, metabolites, peptides) is much slower than ions is now thought to proceed by a different mechanism than diffusion through pores. One model is that the strands of tight junctions are rapidly and sequentially unsealed and resealed to allow stepwise diffusion of some molecules.

Besides junctional complexes, epithelial cells also contain gap junctions to facilitate cell to cell communication and coordinate cellular activities.

Basement Membrane

The basement membrane is form of extracellular matrix that underlies all epithelia. It provides structural support to epithelia and forms a mechanical connection between epithelia and underlying connective tissue. The basement membrane also regulates the metabolism, proliferation, survival and differentiation of epithelial cells. The basement membrane functions as filter and because epithelia lack their own blood supply, all small molecules and gases derived from the blood must diffuse across the basement membrane. The basement membrane also prevents epithelial cells from invading into connective tissue.

There are four major components to the basement membrane. Laminin is trimeric protein that is the primary organizer of the basement membrane as it interacts with itself, the other components in the basement membrane, and with proteins in epithelial cell. Type IV collagen forms felt-like network of fibers that gives the basement membrane its tensile strength. Nidogen and perlecan are two small proteins that link the collagen network to laminin. There are several other components to basement membrane, including fibronectin.

Epithelial cells interact with the basement membrane via integrins along their basal surface. Integrins bind laminin and fibronectin and assemble into patches to increase the strength of the interactions. Some of these patches associate with actin filaments, but some also associate with intermediate filaments and are called hemidesmosomes.

Epithelial Cell Polarity

All epithelial cells are polarized with the apical surface facing the lumen or external environment and the basal surface facing the basement membrane. Clearly, each surface requires a different set of proteins to performs its function. Proteins are targeted to the plasma membrane are sorted in the trans-Golgi network based on signal sequences. These signal sequences guide proteins into a unique set of vesicles that traffic to the apical or basal surface. The signal sequences for the basal surface primarily reside in the protein sequence and often interact with clathrin adaptors that sequester the proteins in clathrin-coated vesicles. The signal sequences for apical surface proteins are more diverse and can be found in the protein or carbohydrates attached to proteins.

In addition to protein sorting in the TGN, epithelial cells utilize transcytosis to maintain polarity. Transcytosis involves formation of endocytic vesicles from the basal surface that are then moved to and fused with the apical surface. Wayward apical proteins can be returned by transcytosis. Transcytosis also allows epithelial cells to transport material from the basal environment to the apical environment. Notably, in the intestine, transcytosis is used to transport antibodies produced by B-cells near the basement membrane into the lumen of the intestine.

The apical and basal plasma membrane are continuous and proteins from one side would rapidly diffuse to the other. Tight junctions prevent mixing of apical and basal proteins by functioning as diffusion barrier. Interestingly, tight junctions also inhibit diffusion of lipids in the plasma membrane but only those in the outer leaflet. Some apical proteins are attached to lipids in the outer leaflet, and tight junctions need to prevent the diffusion of those proteins.

Microtubules play an important role in maintaining cell polarity. In contrast to non-polarized cells where the minus ends of microtubules are found in the center of the cell, microtubules in epithelial cells are oriented with their minus ends toward the apical surface. Epithelial cells can use directionality of motor proteins to transport material to apical and basal surfaces.

Renewal of Epithelial Cells

Epithelial cells are continuously lost due to mechanical and chemical stress and need to be replaced to maintain the integrity of the epithelium. Epithelia contain stem cells capable of proliferating and differentiating into a specific type of epithelial cell. In a stratified epithelium, such as epidermis of skin, stem cells are located in the basal layer of cells. These stem cells differentiate as they migrate toward the outer surface of the epidermis. In a simple epithelium, such as intestine, stem cells reside in the same layer as the differentiated cells, but are localized to special regions (called crypts in intestinal epithelia). As these stem cells differentiate, the migrate out of these specialized regions to replace cells in other areas of the epithelium.

Overview

Epithelia are a sheet of cells that covers most of the body surfaces, forms the functional unit of secretory glands and line the inner surface of blood vessels. Epithelia perform a wide variety of functions and adopt different cellular arrangements and structure to accomplish these functions. Epithelial cells are held together by tight junctions, adhering junction and desmosomes and attach to a specialized form of extracellular matrix called the basement membrane. Epithelial cells are polarized with an apical surface facing the lumen or external environment and a basal surface facing the basement membrane. The apical and basal surfaces have unique biochemical compositions.

Questions

  1. How might strands of tight junctions be disassembled to allow paracellular diffusion of small molecules?
  2. Answer: Tight junctions might be disassembled by dissociating claudins from the actin cytoskeleton. This would allow claudins to more freely diffuse within the plasma membrane and weaken their interaction with claudins in neighboring cells. Alternatively, claudins could be endocytosed to lower their numbers in the plasma membrane, weakening the interaction with neighboring cells.
  3. Renal magnesium wasting is an excessive loss of magnesium in the kidney. Defects in which protein might likely cause this disease?
  4. Answer: Tight junctions and claudins in particular are responsible for limiting the paracellular diffusion of ions and small molecules. A mutation in the claudin 19 are associated with magnesium wasting in the kidney.
  5. Why is the basement membrane important for development and progression of carcinomas?
  6. Answer: The basement membrane separates all epithelial cells from blood vessels and lymphatic vessels, both of which are the conduits through which carcinomas metastasize to other organs or tissues. An intact basement membrane prevents carcinomas from gaining access to blood vessels or lymphatic vessels.
  7. How do vesicles from the trans-Golgi network correctly fuse with either the apical or basal plasma membrane?
  8. Answer: The apical and basal plasma membrane contain a unique set of Rab, tether and SNARE proteins. Vesicles that bud from the TGN and are destined for either the apical or basal surface contain Rabs and SNAREs that match those at either the apical or basal surface.