Epidermal-melanin unit

Fitzpatrick TB et al. 1963

The epidermal melanin unit (EMU) is a term first used by Breathnach and Fitzpatrick in 1963 to describe the organoid functional unit between melanocytes and keratinocytes. This organoid system works synchronously to produce and distribute melanin.

Melanin is synthesized in melanosomes, transported to the dendrite tips and translocated to the keratinocytes where it forms caps over the keratinocyte nuclei. The molecular and cellular mechanisms involved in melanosome transfer and the interactions between keratinocytes and melanocytes required for this process are not yet fully understood.

Possible mechanisms of melanosome transfer include:

• melanosome release and endocytosis
• direct inoculation ("injection")
• fusion of the keratinocyte-melanocyte membranes
• phagocytosis.

Melanocytes and keratinocytes exist in the human epidermis in a truly extraordinary and remarkably stable unit in which a post-mitotic melanocyte is united with approximately 36-40 viable keratinocytes. This functional unit is crucial for maintaining the integrity of the human epidermis and in particular for protective skin pigmentation.

All human "pigment types", regardless of ethnicity and skin color, have the same number of melanocytes per unit area of epidermis. The qualitative difference in human skin color thus results from differences in:

• the number and shape of melanosomes per melanocyte
• the type of melanin
• the pattern of distribution of the melanin granules in the different layers of the human epidermis (Fitzpatrick TB et al. (1963).

Within the epidermis-melanin unit, the keratinocyte partner controls various aspects of melanocyte behavior, including through a regulated balance of paracrine growth factors and cell-cell adhesion molecules (Casalou C et al. 2022).

Pathological changes in the EMU are found, for example, in melanoma. Melanoma cells usually take on an epithelioid form and lack many features of their normal precursors, e.g. the dendriticity of the melanocyte, the solitary distribution between 5-8 normal basal keratinocytes instead of 36-40. In melanomas with a superficial spreading component, there is an intraepidermal, pagetoid growth pattern, often with a pronounced lateral spread of enlarged malignant cells. These can accumulate both at the dermo-epidermal junction and in more superficial epidermal areas of a now disorganized epidermis characterized by the loss of the stable EMU cell ratio with keratinocytes (Casalou C et al. 2022).

Nevus depigmentosus: This disease is characterized by a circumscribed amelanosis. The number of melanocytes is normal or reduced.

Oculocutaneous albinism: Patients with this hypopigmentary disorder have mutations that directly affect the tyrosine gene TYR, or genes of proteins that regulate the processing of the copper-containing enzyme tyrosinase and the biosynthesis of melanin in the melanosomes and the shedding of mature melanosomes into the epidermis. The patients have a normal melanocyte density in their epidermal melanin units. They are very susceptible to carcinoma formation of the skin. However, the occurrence of melanoma in South African albino patients is very rare. The incidence of melanoma in black South African albinos is the same as in black South Africans (American Cancer Society (2022). At first glance, this may seem paradoxical, as eumelanin has a photoprotective effect and its absence or reduction should increase the risk of UVR-associated DNA mutations that are characteristic of melanoma. If a melanoma is found in these albino patients, it is usually an amelanotic melanoma (Ihn H et al. 1993).

Piebaldism: This pigementation disorder is caused by mutations that affect the development and migration of melanoblasts from the neural crest to the skin.In humans, piebaldism is caused by heterozygous "loss-of-function" mutations of the KIT gene. The mutations of cKIT that have been identified in piebaldism patients range from gross deletions to missense defects and are all inherited in an autosomal dominant manner, leading to a loss of melanocytes in the skin.

Psoriasis: The integrity of the epidermal melanin unit is also disrupted in psoriasis (Nickoloff BJ 2004). It has been reported that melanocytes in the epidermis of lesional and perilesional psoriasis can actually proliferate (Casalou C et al. 2022). Epidermal melanocyte proliferation in psoriasis may be related to the massive keratinocyte hyperplasia that characterizes psoriasis, leading to extreme elongation of the rete ridges of the epidermis and thus to a massive increase in the surface area of the basal layer where the melanocytes are located. Remarkably, there is no increased risk of melanoma formation in psoriasis. This is all the more remarkable as psoriasis patients are often treated with PUVA (psoralen and UVA) over long periods of time (Casalou C et al. 2022).

The term "epidermal melanin unit", which has now become commonplace, is inherently incorrect because it does not refer to a ratio of melanin and epidermis but to a melanocyte/keratinocyte quotient.

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