FUERZAS PRIMARIAS

The skin is composed of three main layers: the hypodermis, dermis and epidermis (Figure 1.3). The hypodermis, or subcutaneous layer, is the deepest layer of the skin, and consists mainly of adipose and connective tissue. It contains high fat storage capacity, and thus provides cushioning and insulation, as well as skin stability by connecting the dermis to internal organs (Farage et al., 2007). The dermis is the scaffolding component of the skin, and it is mainly composed of collagen and elastin fibres, as well as fibroblasts, blood vessels, lymph vessels and sweat glands (Fore, 2006). Immune cells also reside in the dermis, including mast cells, macrophages, dendritic cells, innate lymphoid cells (e.g. natural killer cells) and T cells, all of which orchestrate to prevent pathogen invasion (Heath and Carbone, 2013). For example, natural killer cells, which are present in small numbers in healthy skin, are involved in viral immunity and also play a role in tumour immunosurveillance (Heath and Carbone, 2013). Dendritic cells also play a role in protecting against viral infections, and are also important for presenting antigens to induce CD8+ (cytotoxic) T cell responses (Shortman and Heath, 2010). Moreover, the skin contains a large number of memory T cells of both the CD4+ (i.e. T-helper cells) and CD8+ subsets, which are located in the dermis and epidermis, respectively, enhancing protection against local infection (Heath and Carbone, 2013).The dermis also contains hair follicles and nerve fibres; the latter project into the epidermis, allowing the skin to transmit sensory information. Moreover, the blood supply within the dermis is responsible for providing circulatory support and nutrients to the epidermis, since the latter does not have its own blood supply (Fore, 2006). The epidermis is the outermost layer of the skin, and consists primarily of keratinocytes organised in a stratified epithelium (Rittie and Fisher, 2015). Proliferating keratinocytes are located in the basal layer of the epidermis (stratum basale), and their proliferative capacity is lost as they differentiate and migrate up the epidermis towards the stratum corneum. The latter is the outermost layer of the epidermis, and is composed of terminally differentiated keratinocytes, also known as corneocytes. These cells are flattened and anuclear but are rich in proteins, and are embedded in a lipid-rich extracellular matrix,

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which provides an impermeable barrier, preventing water loss and entry of pathogens through the skin (Elias et al., 1977). Eventually, corneocytes are shed off the skin surface through a process known as desquamation, completing the cycle of epidermal differentiation (or keratinisation), which occurs approximately every 28 days (Marks, 2004). Moreover, Langerhan cells, which are antigen presenting cells, can also be found in the epidermis. These dendritic cells are involved in skin immunosurveillance by extending their dendrites upwards towards the cornified epithelial layer and sampling external antigens, and this has been shown to be important for priming immunity against skin pathogens (Chomiczewska et al., 2009; Heath and Carbone, 2013). The epidermis is also composed of melanocytes, which comprise approximately 1-2% of epidermal cells, and are present at a ratio of 1:10 melanocyte to keratinocytes. This ratio is maintained constant throughout life, and although the mechanisms controlling this are still poorly understood, it is believed that keratinocytes regulate melanocyte numbers through growth factors and other cell-surface molecules (Scott and Haake, 1991; Haass and Herlyn, 2005). Melanocytes are dendritic cells that reside in the basal layer of the epidermis, and produce the photoprotective pigment, melanin, in response to UV irradiation (Sklar et al., 2013). Melanocytes then transport melanin, which is packaged in vesicles called melanosomes, to surrounding keratinocytes through their dendrites. It has been shown that one melanocyte can transport melanin to approximately 36 neighbouring keratinocytes, and this interaction is also known as the epidermal melanin unit (Fitzpatrick and Breathnach, 1963; Haass and Herlyn, 2005). Unlike keratinocytes, epidermal melanocytes are very long-lived cells, and proliferate extremely rarely once they reach terminal differentiation (Cichorek et al., 2013). A small percentage of dividing melanocytes has been shown in human and mouse skin (Jimbow et al., 1975). Moreover, a subpopulation of differentiated melanocytes that are capable of undergoing division has been identified in zebrafish, however, the proportion of new pigmented cells arising from differentiated melanocytes was very small (4.6%) (Taylor et al., 2011). It is also thought that differentiated melanocytes contribute in part to re-pigmentation in wound healing and vitiligo (Hirobe, 1988; Falabella, 2009). However, new melanocytes arise mainly from a population of undifferentiated melanocytes, which also contribute to the increase in epidermal melanocyte number following exposure to UV irradiation in mice (Kawaguchi et

al., 2001; van Schanke et al., 2005; Walker et al., 2009; Tanimura et al., 2011). Although the

niche of melanocyte stem cells in the adult skin remains to be established, evidence suggests that the bulge area of hair follicles serves as a reservoir for such cells (Nishimura et al., 2002; Nishimura, 2011; Tanimura et al., 2011). However, studies suggest that a melanocyte stem cell niche can also be found in the dermis (Toma et al., 2005; Davids et al., 2009).

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The epidermis also projects inwards towards the dermis, alternating with shallower protrusions back into the epidermis, such that the dermis and the epidermis interconnect via invaginations, giving rise to the rete ridges. These structures provide mechanical support for the epidermis, and are also important for nutrient exchange, as they increase the surface area of the epidermis which is exposed to capillaries and venules circulating near the epidermal-dermal junction (EDJ) (Briggaman and Wheeler, 1975).

Figure 1.3 - Layers of the human skin. The innermost layer of the skin is the hypodermis, or

subcutaneous layer, which is mainly composed of adipose tissue and acts as a shock absorber as well as providing insulation. The dermis connects the hypodermis to the epidermis, and has a high content of collagen and elastin fibres, providing strength, elasticity and support to the skin. The dermal compartment also harbours blood vessels, which supply nutrients to the epidermis, as well hair follicles and sweat glands. Moreover, nerves present within the dermis also make connection with the EDJ, and relay sensory information. The epidermis is the outermost layer, and is mainly composed of keratinocytes, which are constantly being turned over and shed off, providing an impermeable barrier to the skin. Melanocytes also reside within the basal layer of the epidermis, and they produce melanin when exposed to UV irradiation. Melanocytes interconnect with surrounding keratinocytes via dendrites, which mediate melanin transport to neighbouring cells, providing protection against the harmful effects of UV irradiation. Image obtained from (Winslow, 2008).

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