What’s the body’s biggest organ?
You may be surprised to find out that it’s the skin, which you might not think of as an organ. It has a total area of 22 square feet in adults, weighing approximately 5 kilograms!
So why do we require all this skin? Aside from keeping our bones, muscles and organs nicely tucked away, it plays a number of vital functions which we simply could not survive without. It protects us against UV light, dehydration and invasion by micro-organisms, allows us to have a sense of touch, is involved in regulating our core body temperature, acts as a water-barrier and is essential for the production of vitamin D.
The skin is composed of two layers, each having very different functions. These layers include the epidermis and the dermis. Just below the skin is another layer called the hypodermis.
Relative positions of the epidermis, dermis and hypodermis
PAS+ staining showing the epidermis, dermis and hypodermis
Let’s start with the most simple layer and work our way up. The hypodermis contains fat lobules (except in the eyelids), which are a good insulator, and loose connective tissue with blood vessels interspersed. We need this layer in order to attach our skin to the underlying bone and muscle, as well as to transport blood to the dermis.
The dermis is the inner layer of the skin, primarily composed of collagen for strength and elastic fibres for flexibility. Its main function is to support the epidermis. To fulfil this function, small finger-like projections, collectively known as papillae (just one is called a papilla), are present in the uppermost portion of the dermis. The papillae anchor the dermis onto the epidermis, preventing them from separating and supplies the lower epidermis with oxygen. The latter is possible since blood vessels from the hypodermis extend into the dermis. The skin needs a blood supply in order to bring nutrients and oxygen in as well as to remove waste products and carbon dioxide, and this requires a network of blood vessels. These vessels also provide an access route for immune cells to provide defence against infection. A thin layer of tissue called the basement membrane seperate the dermis from the epidermis.
Image showing the papillae
Image showing the papillae
Also present in the dermis are structures known as hair follicles and sebaceous glands. These structures are types of skin appendages. A hair follicle is a structure in which hair grows, and a sebaceous gland is a structure which produces sebum. More on those in the next lesson.
The epidermis, which is the thinnest layer of the skin and the most complex, is the part of your skin that you can see. It has a ridged and patterned surface, clearly visible on your fingertips. When looking at your hands, even though you can’t see anything happening, your epidermis is hard at work. To understand what is happening, we must first discuss the types of cells present in the epidermis.
Keratinocytes are the predominant cell type present in the epidermis, constituting 90% of the cells found there. Keratinocytes are so called because they contain large amounts of the protein keratin which is needed to provide physical protection, strength and rigidity to the cells. To exemplify the strength of keratin, think of an animal horn. Between adjacent keratinocytes, cell-to-cell adhesions called desmosomes exist, helping the skin resist shearing forces. As keratinocytes mature and die, completing their terminal differentiation programme, they become corneocytes. They have lost their cell nuclei and have become flatter.
Now you know the basic mechanics of these cells, let’s look at the structure of the epidermis closer. The cells in the epidermis form a multi-layered system, with the different layers having distinct differences. The number of distinct layers present in the acne prone areas is four (a fifth layer is present on the palms and soles).
Layers of the epidermis
So how do these distinct layers form? The story starts in the very lowest layer of the epidermis (called the stratum basale) where new skin cells are forming, which is one cell thick when everything is going to plan. The cells in this layer are called basal keratinocytes. They are stem cells. When they divide, each of the two resulting daughter cells have a choice. They can either remain a stem cell in the lower one cell thick epidermal layer or they can begin to migrate through the epidermis, continually maturing and changing in structure via a process called terminal differentiation . To maintain a stable stem-cell population as well as to allow the skin to be renewed, one basal keratinocyte remains behind whilst the other undergoes terminal differentiation.
Cell division by basal keratinocytes
The differentiating cells are the keratinocytes. When they have finished their terminal differentiation program they are called corneocytes, which are dead flattened cells with no nucleus or cell organelles, as previously discussed. Why does this happen? Well, as we already know the dermis has an active blood supply whereas the epidermis does not. The papillae protruding from the dermis provides the lower layers of the epidermis with nutrients via diffusion. This means that the upper layers of the epidermis, where cells are closer to the skin surface, are without nourishment. So, what you see on your own hands is actually dead skin cells. How do the keratinocytes migrate? As newer keratinocytes form at the bottom of the epidermis, older ones are forced upwards towards the skin surface. To accommodate the new skin cells and to allow the skin to be constantly renewed, corneocytes are shed from the skin surface. We will now look at the different layers of the epidermis in closer detail.
The uppermost paper-thin layer of the epidermis, the layer in which you can see, is called the stratum corneum and is composed of 18-20 layers of corneocytes, depending on the anatomic location. The space between these stacked corneocytes is filled with a complex mixture of lipids comprised of ceramides, cholesterol and free fatty acids. These lipids provide the characteristic permeability barrier of the stratum corneum, preventing the entry of water and water-soluble substances . The structure of the stratum corneum can be compared to brick and mortar. The corneocytes are bricks and the lipids are mortar. Corneodesmosomes, which are modified desmosomes, function as ‘rivets’, holding the keratin-filled corneocytes together [3,4]. The corneodesmosomes between the outermost corneocytes gradually degrade via the action of a protease enzyme, enabling them to be shed off as squames in a process called desquamation. Millions of these dead cells are shed off daily. It typically takes 28 days for a newly born keratinocyte to be shed as a corneocyte. Our understanding of the mechanisms that control the degradation of corneodesmosomes is limited.
The next layer is called the stratum granulosum and is typically three to five cells thick. The upper stratum granulosum is linked with the lower stratum corneum by desmosomes. Keratinocytes within this layer synthesise lamellar granules which are then secreted as they approach the top of the layer, themselves losing their nuclei and their shape, resembling grains of rice. This means that the junction between the stratum granulosum and the stratum corneum is rich in these lamellar granules, occupying about 20% of the cell volume.
When we discussed the stratum corneum we learnt that a complex mixture of lipids existed between the corneocytes. These lipids were released by the lamellar granules. The protease enzyme which degrades corneodesmosomes allowing desquamation to occur as well as anti-microbial peptides (such as beta defensins and cathelicidins) are also released. The latter links the formation of a permeability barrier with an anti-microbial barrier, both important functions we discussed in the introduction. This is essential since the epidermis suffers more direct, frequent, and damaging encounters with the external world than any other tissue in the body. Another protein manufactured by the keratinocytes in the stratum granulosum is called filaggrin. It is stored in keratohyalin granules within the keratinocytes. These granules are secreted in the same way as lamellar granules are. Filaggrin helps the stratum corneum retain moisture.
Keratinization, which is the process by which keratinocytes begin to produce keratin, begins in the stratum spinosum, the next layer of the epidermis. This layer is composed of polyhedral keratinocytes which have a large nuclei since they are active in synthesizing keratin. As the keratinocyte continues to move up the layer, keratin accumulates over time within the cell. As the keratinocyte reaches the stratum granulosum, the keratin within the cell aggregate together, in the presence of filaggrin, forming tonofibrils. These tonofibrils are what form desmosomes, linking the adjacent keratinocytes together until they are ready to be shed as worn-out corneocytes. The role of keratin is not just to produce the desmosomes. Keratin itself is a strong fibrous protein, forming a mesh. This mesh is able to hold water, hence aiding in retaining moisture within the skin, keeping the epidermis lubricated and resistant to cracking.
The next layer is called the stratum spinosum. It contains a large proportion of immune cells called Langerhans cells which are a type of antigen-presenting cell. As the name suggests, these cells present antigens, which is any foreign substance, to other immune cells. In the healthy epidermis they are the only type of antigen-presenting cell present and their role is to keep unknown particles from infiltrating deep into the skin.
The deepest layer of the epidermis, which is where the basal keratinocytes are found as previously discussed, is called the stratum basale. These basal keratinocytes are attached to the basement membrane, which is the thin layer of tissue separating the epidermis from the underlying dermis, by a special type of desmosome called a hemidesmosome. These basal keratinocyte stem cells divide to form the keratinocytes of the stratum spinosum which migrate until they reach the skin surface and undergo desquamation.
Layers of the epidermis