Epithelial Tissue

Epithelia are evolutionary conserved and ubiquitous in multicellular organisms. They form a barrier between the external and the internal environment, as the cells are tightly linked in an uninterrupted sheet, lining the external-facing surfaces of tissues and organs. The epithelium is structurally robust to maintain a barrier that withstands the harsh conditions of its outside environment. What determines the function and the properties of each epithelium type, is moderated by cell-cell junctions, meaning that any form of irregularity in the structure or function of these junctions can be considered as a common factor in genetic and metabolic disorders.

## Origin of epithelial cells[1]

Epithelial cells are derived from the 3 embryonic layers. The endoderm develops into most of the digestive system and the epithelium lining of the airways. The mesoderm creates the endothelium where epithelial cells line blood vessels. The Ectoderm develops into the epithelial lining of the skin, mouth, nose as also anus. [1]

Cell shapes: Squamous, Cuboidal, Columnar

Cell Layer: Simple, Stratified, Pseudostratified, Transitional

Epithelial tissues line the surfaces of skin, digestive organs and respiratory organs. Some examples of epithelial tissue include:

**Simple squamous epithelium:** Single layer of flat and often thin cells, allowing simple diffusion of materials. Located in the kidneys, blood vessels and air sacs of the lungs.

**Simple cuboidal epithelium :** a single layer of cube-like in shape cells, allow secretion and absorption and are located in the kidneys, the ovaries and various glands.

**Simple columnar epithelium:** a single layer of tall and column like cells, allowing absorption and secretion with the help of mucus and cilia. These cells are located in the digestive tract, glands, bronchi and uterus.

**Pseudostratified columnar epithelium:** is a single layer of cells, that vary in height and allow secretion and movement of mucus, located in the windpipe.

**Stratified squamous epithelia:** More than one layer of epithelial cells, protecting the underlying tissue from abrasion. The tougher type, that contains the protein keratin, is located in the dry upper layer of the skin. The non-keratinised, is located in the moist parts of the mouth, oesophagus, vagina, urethra and anus.

**Stratified cuboidal epithelium:** More than one layer of cells, having a cube-like shape, allowing protection of glands and are located around the mammary glands, saliva glands and sweat glands.

**Stratified Columnar epithelium:** More than one layer of tall and column shaped cells, allowing protection and secretion. These type of cells are not common in the human body, only found in the male urethra and associated with certain glands.

## **Cell junctions** and Extracellular Matrix

Cell junctions are protein complexes that establish membrane polarity, anchor epithelial tissue to the connective tissue found underneath as also connect adjacent cells.

Cells may be linked by direct interactions, or they may be held together within the extracellular matrix, a complex network of proteins and polysaccharide chains that the cells secrete. By one means or another, cells must cohere if they are to form an organized multicellular structure that can withstand and respond to the various external forces that try to pull it apart

## Cell-Cell junctions

### Anchoring junctions

Anchoring junctions mechanically attach cells and their cytoskeletons to their neighbouring epithelial cells through strong and resilient membrane-spanning structures that are threaded inside the cell to the tension bearing filaments of the cytoskeleton. Anchoring junctions are made up from two types of proteins. The transmembrane adhesion proteins and the intracellular anchor proteins. The transmembrane adhesion protein binds to one or more intracellular anchor proteins through its cytoplasmic tail and it also interacts through its extracellular domain with the extracellular matrix or the extracellular domains of another cell. The second protein is the intracellular anchor protein that binds actin filaments or intermediate filaments to the junctional complex.

#### **Cadherins cell- to-cell junctions (Adherenes and Desmosomes)**

One of the two functionally different forms of anchoring junctions are the cadherin family. These transmembrane adhesion proteins, form adherens junctions and desmosomes which hold the epithelial cells together. Homophilic binding occurs between the N-terminal tips of Cadherin molecules on one cell to the adjacent cell, forming a knob to pocket connection. The cadherin cell-cell binding is highly selective therefore, only similar type of cells stick together. The formation of epithelium is a reversible process and depends on transcription regulatory proteins, Twist, Slug and Snail. In an increase of the transcription regulatory protein, Twist, causes the conversion of epithelial cells to mesenchymal character, whereas switching Twist off, has the opposite effects. This happens because Twist, inhibits the expression of cadherins, for example E-cadherin, that holds epithelial cells together. In epithelia adherens junctions form adhesion belt underneath the tight junction, that lines the circumference of each of the interacting cells in the epithelial layer. Next to the adhesion belt, actin filaments are found, that attach to the memrbane through α-catenin, vinculin, catenins which are anchor proteins. Desmosomes link intermediate filaments of adjacent cells into a net. The desmosomes of most of epithelia are made of Keratin filaments while in heart muscle cells are made up of desmin filaments. Adhesion proteins are linked to the cytoskeleton through the desmoplakin and plakoglobin, which are intercellular anchor proteins. [2]

### Occluding Junctions

Tight junctions between epithelial cells have two major roles. They act as barrier to the diffusion of lipids and some membrane proteins between basolateral and apical domains of the plasma membrane and they seal adjacent epithelial cells tightly together so that, low-molecular weight molecules will not pass through the tight junction. The permeability of the tight junctions, varies between different types of epithelium lining. For example the permeability of the epithelium lining in the small intestine is higher than the epithelium lining of the urinary bladder. These differences are due to the differences in the tight junction proteins that make up the junctions. From freeze- fracture electron microscopy, tight junctions are shown to be composed of a network of sealing strands, with each strand acting as a barrier to ion flow. Long row of transmembrane adhesion proteins such as claudins and occludins found in each of the two interacting plasma membranes, compose each sealing strand and are associated with ZO peripheral membrane proteins. Claudins play an important role in tight junction formation and function by regulating paracellular barrier permeability. [3]

### Channel-forming junctions

Gap junctions allow inorganic ions to pass from the cytoplasm of one cell to another allowing communication between neighbouring cells within the tissue. The gap is lined by six channel-forming proteins called connexins, forming connexons that couple the cells both metabolically and electrically.

## Cell-matrix junctions

### Anchoring junctions

Another large family of adhesion proteins are the integrins, which are the second form of anchoring junctions. Integrins link to actin filaments, forming focal adhesions, enabling epithelial cells to bind on the extracellular matrix (ECM). Hemidesmosomes are very alike to desmosomes and act as strong connections to distribute sheering and tensile forces through an epithelium. However hemidesmosomes instead of binding adjacent cells, they connect basal surface of epithelial cell to the basal lamina. Anchor protein plectin, binds keratin intermediate filaments to intracellular domain. Whereas the extracellular domain binds to laminin protein in the basal lamina. (Figure 2)[4]

## Integrins and Cell polarity

During establishment of cell polarity, integrins provide a central role in the interaction of cells with their extracellular environment [5, 6]. Particularly there are three multiproteins complexes involved. The Par, Scribble and Crumbs proteins. During the integrin- extracellular binding Rac1- dependent pathway is initiated that stimulates the production of basal actin cortex and laminin is assembled (Figure 3) [7,8]

Further information on cell polarity and tissue architecture can be found here and here

## Summary

Epithelia can be classified as single layered or multilayered and can be derived from endoderm, mesoderm and ectoderm. Epithelia during development, begin as a sheet of cells that adhere to the basement membrane, which is reach in growth factors and extracellular matrix (ECM). ECM and growth factors are deposited at the underlying mesenchyma and the interface of the epithelium. Integrins bind to the Extracellular matrix ligands in the basement membrane and link to cellular cytoskeleton. Cell differentiation, migration and stratification occurs due to regulation of the detachment and adhesion of cells and their underlying ECM, by hemidesmosome and adhesion junctions. Intercellular connections are achieved due to the formation of desmosome, tight and adherens junctions. These junctions enable the communication and the sheet of epithelial cell formation. Finally integrins are shown to have a major role in cell polarity and the interaction of cells with their extracellular environment.

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**References and extra reading :**

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1. Blanpain, C., Horsley, V., Fuchs, E. 2007. Epithelial Stem Cells: Turning over New Leaves. *Cell* 128(3), pp. 445-458. doi: 10.1016/j.cell.2007.01.014
2. Guillot, C., Lecuit, T. 2013. Mechanics of Epithelial Tissue Homeostasis and Morphogenesis. *Science (American Association for the Advancement of Science)* 340(6137), pp. 1185-1189. doi: 10.1126/science.1235249
3. Garcia, M.A., Nelson, W.J., Chavez, N. 2018. Cell–cell junctions organize structural and signaling networks. *Cold Spring Harbor perspectives in biology* 10(4), pp. a029181. doi: 10.1101/cshperspect.a029181
4. Alberts, B. et al. 2015.  *Molecular biology of the cell*. 6th edition. New YorK, Abingdon: Garland Science, Taylor and Francis Group
5. Bryant, D.M., Mostov, K.E. 2008. From cells to organs: building polarized tissue. *Nature reviews. Molecular cell biology* 9(11), pp. 887-901. doi: 10.1038/nrm2523
6. Xavier de Silveira dos Santos, A., Liberali, P. 2019. From single cells to tissue self-organization. *The FEBS journal*286(8), pp. 1495-1513. doi: 10.1111/febs.14694
7. Lee, J.L., Streuli, C.H. 2014. Integrins and epithelial cell polarity. *Journal of cell science* 127(15), pp. 3217-3225. doi: 10.1242/jcs.146142
8. Roignot, J., Peng, X., Mostov, K. 2013. Polarity in Mammalian Epithelial Morphogenesis. *Cold Spring Harbor Perspectives in Biology* 5(2), pp. a013789. doi: 10.1101/cshperspect.a013789

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EXTRA READING

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* Charras, G., Yap, A.S. 2018. Tensile Forces and Mechanotransduction at Cell–Cell Junctions. *Current biology* 28(8), pp. R445-R457. doi: 10.1016/j.cub.2018.02.003
* Harris, A.R., Daeden, A., Charras, G.T. 2014. Formation of adherens junctions leads to the emergence of a tissue-level tension in epithelial monolayers. *Journal of cell science* 127(11), pp. 2507-2517. doi: 10.1242/jcs.142349
* Atlas of Human Histology. 2014. *Chapter 2 - Epithelium.* Available at: https://histologyguide.com/slidebox/02-epithelium.html [Accessed: 20 March 2022].