**1. Introduction**

#### **1.1. Skin and melanocytes**

Skin is composed of three layers: epidermis, dermis and hypodermis. The epidermis is organized into five layers in which there are different cell types. The most important cell type in the epidermis is the keratinocytes which constitute approximately 95 % of the total epider‐ mal cells. Melanocytes, Langerhans cells, Merkel cells and inflammatory cells form the remaining 5 % [1]. Among these cells, the melanocytes, which are dendritic cells, are the second most important cell type in the epidermis. They have the capacity to synthesize melanin, a skin pigment. Melanocytes are not only found in the skin, but can also be observed in hair, eyes, ears and central nervous system (Table 1) [2-3]. Their different localization gives them different functions in the organism, but they all keep a common function: melanogenesis [1].

#### *1.1.1. Skin melanocytes*

Skin melanocytes are localized in the basal layer of the epidermis, at the junction of the dermis, and their dendrites expand between keratinocytes of the next layer. These dendrites allow melanocytes to make contact with the keratinocytes for the melanin transfer. This cell-to-cell contact stimulates proliferation and differentiation of melanocytes due to growth factors produced by the keratinocytes [4]. Thus, the melanosome, organelle containing melanin pigments, can be transferred to the adjacent keratinocytes, which store the pigments, and degrade them when they move to the skin surface [5]. When the pigments are in keratinocytes, they give a color to the skin with a mix of other pigments such as carotenoids and hemoglobin derivatives [6-7]. However, melanin is the principal pigment present in the skin [7] and can be

© 2013 Gendreau et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


**Table 1.** Melanocyte functions dependent on the body localization

found in two different colors: yellow/red (pheomelanin) and brown/black (eumelanin) [8]. These two types of pigment are one of the explanations for different ethnic skin color in the world. The other causes will be covered in the next section. However, ultraviolet radiations (UVR) are the main factor causing pigmentation variation in the skin. They can produce photodamage, erythema, mutations, vitamin D synthesis and tanning of the skin. Current research on the mechanism of UV-induced pigmentation (tanning) suggests that UVR induced DNA damage, and the mechanism for repair of these damages by a specialized endonuclease increases the production of melanin [6, 9]. This quantity of produced melanin acts as a skin protective barrier against the UVR by absorbing the UV photons [10]. Some research demon‐ strates that people who have more pigmented skin have less risk of developing skin cancer or sunburn. Moreover, eumelanins, which are presented in high quantity in dark skin, are more photoprotective than pheomelanins. They absorb free radicals generated in the cells by UVR, thus preventing DNA damage [11].

#### *1.1.1.1. Ethnic skin types*

The different ethnic skin color worldwide depends on various factors such as UV exposition, genetics, environmental factors and skin pigments [12]. Melanin is the principal pigment which can affect skin color in several ways. The number of melanocytes, the melanogenic activity, the melanin type, the size and the number of melanosomes and the distribution in the epidermis can also affect the skin pigmentation [6]. In 2002, Alaluf *et al*. demonstrated that Causasian skin was characterized by a low number of melanocytes (1 for 36 keratinocytes), small melanosomes and light pigments such as pheomelanins while black skin was charac‐ terized by the presence of a higher number of melanocytes, larger melanosomes, a higher quantity of melanin and more eumelanins [13]. It seems that the size of melanosomes is important in the skin pigmentation because large melanosomes are found in the epidermis as single particles, while small melanosomes tend to aggregate them. It could have the effect that the large melanosomes are transferred to keratinocytes individually and thus, can absorb light better than melanosomes transferred in complex [14].Their distribution in the epidermis is equally very important and research demonstrated that in white skin, melanosomes are completely degraded before the *stratum corneum* while in dark skin, melanosomes are found in this layer [15]. Therefore, all these characteristics contribute to ethnic groups their specific skin color.

#### *1.1.2. Other melanocytes*

found in two different colors: yellow/red (pheomelanin) and brown/black (eumelanin) [8]. These two types of pigment are one of the explanations for different ethnic skin color in the world. The other causes will be covered in the next section. However, ultraviolet radiations (UVR) are the main factor causing pigmentation variation in the skin. They can produce photodamage, erythema, mutations, vitamin D synthesis and tanning of the skin. Current research on the mechanism of UV-induced pigmentation (tanning) suggests that UVR induced DNA damage, and the mechanism for repair of these damages by a specialized endonuclease increases the production of melanin [6, 9]. This quantity of produced melanin acts as a skin protective barrier against the UVR by absorbing the UV photons [10]. Some research demon‐ strates that people who have more pigmented skin have less risk of developing skin cancer or sunburn. Moreover, eumelanins, which are presented in high quantity in dark skin, are more photoprotective than pheomelanins. They absorb free radicals generated in the cells by UVR,

Skin Skin pigmentation

Hair Hair pigmentation Eyes Vision

Ears Hearing

Central nervous system Scavenge toxic cations

**Table 1.** Melanocyte functions dependent on the body localization

**Functions**

Photoprotection

Photoprotection Eye pigmentation

Protection against high intensity noise

The different ethnic skin color worldwide depends on various factors such as UV exposition, genetics, environmental factors and skin pigments [12]. Melanin is the principal pigment which can affect skin color in several ways. The number of melanocytes, the melanogenic activity, the melanin type, the size and the number of melanosomes and the distribution in the epidermis can also affect the skin pigmentation [6]. In 2002, Alaluf *et al*. demonstrated that Causasian skin was characterized by a low number of melanocytes (1 for 36 keratinocytes), small melanosomes and light pigments such as pheomelanins while black skin was charac‐ terized by the presence of a higher number of melanocytes, larger melanosomes, a higher quantity of melanin and more eumelanins [13]. It seems that the size of melanosomes is important in the skin pigmentation because large melanosomes are found in the epidermis as single particles, while small melanosomes tend to aggregate them. It could have the effect that the large melanosomes are transferred to keratinocytes individually and thus, can absorb light better than melanosomes transferred in complex [14].Their distribution in the epidermis is equally very important and research demonstrated that in white skin, melanosomes are

thus preventing DNA damage [11].

**Body localization**

760 Regenerative Medicine and Tissue Engineering

*1.1.1.1. Ethnic skin types*

#### *1.1.2.1. Hair and eye melanocytes*

Melanocytes have a predominant role in skin color, but they have equally the same function in hair and in eyes. In hair, they are localized in the bulb, at the bottom of the hair follicles, to give the hair's color. The same pigments found in skin, such as pheomelanin and eumelanin, are also responsible for the different colors. Counter to skin melanocytes that rarely proliferate, hair melanocytes can proliferate and differentiate in each hair cycle. This cycle includes the growing phase (anagen) in which there is melanogenic activity and hair is pigmented. At the end of this phase, the hair follicle regresses, the melanogenic activity decreases and the melanocytes retract their dendrites to finally stop the pigmentation. These non-active mela‐ nocytes are replaced by new melanocytes, which are recruited from the pigment cell reservoir, to restart a new hair cycle [16]. In eyes, there are two types of melanocytes: conjunctival and uveal. The first type is localized in the conjunctiva and transfers melanin to conjuctival epithelium while the second is localized in the iris and produces as well as stores melanin, but it does not transfer melanin to any other cells [17]. The quantity or the type of melanin in uveal melanocytes characterizes different eye colors. Such as in the skin, melanin contains in uveal melanocytes may have a protective role for the eyes against UVR. However, few studies have been conducted on this subject and uveal melanocytes remain unknown.

#### *1.1.2.2. Ear and central nervous system melanocytes*

Melanocytes have a well-known pigmentation function, but they also have an important role in ears and in the central nervous system. Melanocytes in ears are located in the stria vascularis of the cochlea, which is formed of three cell types: marginal cells, basal cells and intermediate cells [18]. Intermediate cells are composed of two types of melanocytes, such as light cells that are able to synthesize melanin, and dark cells that are incapable. They are necessary to the normal function of ears, and damages or loss of these cells can cause the hearing loss [19]. Some studies demonstrated that albino guinea pigs are more sensitive to high intensity of noise than pigmented guinea pigs because of their low quantity of melanocytes [20]. In the nervous central system, melanocytes are distributed on the meninges, particularly on the leptomeninges that cover the brain. Their role in the organism is not yet well-determined, but it is known that leptomeninge melanocytes have the capacity to capture toxic cations and free radical species from the blood circulation [19].

#### *1.1.3. Melanogenesis*

Melanocytes originate in neural crest precursor cells: the melanoblasts. Melanoblasts migrate, proliferate and differentiate into melanocytes to reach their destination, such as skin, eyes, hair, meninges and ears [3]. Melanin is synthesized in these melanocytes in specialized lysosomelike organelles named melanosomes. These organelles have four stages of maturation in which the melanosome begins unpigmented and ends pigmented [5]. The process of melanin synthe‐ sis is called melanogenesis and it needs three enzymes to assure its good working: tyroninase, tyrosinase-relatedprotein1(TRP1)andtyrosinase-relatedprotein2(TRP2).Thesethreeenzymes are necessary for the regulation of the melanogenesis, but tyrosinase is the limiting factor of this pathway. It catalyzes the first two reactions of the biosynthesis of melanin that are necessary for producing eumelanin and pheomelanin [21] while TRP1 and TRP2 are only involved in the pathway of eumelanin [1]. Tyrosinase uses tyrosine, DOPA and 5,6-dihydroxyindole (DHI) as substrate to produce respectively DOPA, DOPA-quinone and DHI-melanins (Figure 1). Tyrosinase activity is regulated by some factors such as the pH, which needs to be optimal at 6.8 in melanosomes [22], and the melanocyte-stimulating hormone (α-MSH) secreted by melano‐ cytes. The α-MSH binds melanocortin receptor-1 (MC1R), which is expressed by melanocytes, and triggers eumelanin pigments production whereas when α-MSH does not recognize MC1R, pheomelanin pigments are generated [9]. Following this production of melanin, the melano‐ someswhichhavepigmentsaretransportedtowards theendofthemelanocytedendritebyactin and tubulin filaments. Then, melanosomes are transferred to keratinocytes (when it is skin melanocytes).Themechanismoftransferis stillunknown,butthereexist somehypothesisabout this mechanism such as cytophagocytose [23], discharge melanin in the intercellular space [24], or transfer by filopodia [25]. Once in keratinocyte, melanosomes are distributed around the nuclei and, in response to UVR, they form a supranuclear melanin cap on the sun-exposed side of the nuclei to protect DNA against the UVR damages [26]. Melanin pigments are degraded with the keratinocytes when they move to the epidermal surface for their differentiation [11].

**Figure 1.** Melanogenesis mechanism. TRP1: Tyrosinase-related protein 1; TRP2: Tyrosinase-related protein 2; DHI: 5,6 dihydroxyindole; DHICA: 5,6-dihydroxyindole-2-carboxylic acid.

#### **1.2. Pigmentation diseases**

like organelles named melanosomes. These organelles have four stages of maturation in which the melanosome begins unpigmented and ends pigmented [5]. The process of melanin synthe‐ sis is called melanogenesis and it needs three enzymes to assure its good working: tyroninase, tyrosinase-relatedprotein1(TRP1)andtyrosinase-relatedprotein2(TRP2).Thesethreeenzymes are necessary for the regulation of the melanogenesis, but tyrosinase is the limiting factor of this pathway. It catalyzes the first two reactions of the biosynthesis of melanin that are necessary for producing eumelanin and pheomelanin [21] while TRP1 and TRP2 are only involved in the pathway of eumelanin [1]. Tyrosinase uses tyrosine, DOPA and 5,6-dihydroxyindole (DHI) as substrate to produce respectively DOPA, DOPA-quinone and DHI-melanins (Figure 1). Tyrosinase activity is regulated by some factors such as the pH, which needs to be optimal at 6.8 in melanosomes [22], and the melanocyte-stimulating hormone (α-MSH) secreted by melano‐ cytes. The α-MSH binds melanocortin receptor-1 (MC1R), which is expressed by melanocytes, and triggers eumelanin pigments production whereas when α-MSH does not recognize MC1R, pheomelanin pigments are generated [9]. Following this production of melanin, the melano‐ someswhichhavepigmentsaretransportedtowards theendofthemelanocytedendritebyactin and tubulin filaments. Then, melanosomes are transferred to keratinocytes (when it is skin melanocytes).Themechanismoftransferis stillunknown,butthereexist somehypothesisabout this mechanism such as cytophagocytose [23], discharge melanin in the intercellular space [24], or transfer by filopodia [25]. Once in keratinocyte, melanosomes are distributed around the nuclei and, in response to UVR, they form a supranuclear melanin cap on the sun-exposed side of the nuclei to protect DNA against the UVR damages [26]. Melanin pigments are degraded with the keratinocytes when they move to the epidermal surface for their differentiation [11].

762 Regenerative Medicine and Tissue Engineering

Tyrosine

DOPA

Tyrosinase

Leuco-DOPA-chrome DOPA-chrome DHICA DHI

TRP1 Tyrosinase

**Eumelanins**

**Figure 1.** Melanogenesis mechanism. TRP1: Tyrosinase-related protein 1; TRP2: Tyrosinase-related protein 2; DHI: 5,6-

DHICA Eumelanins DHI Eumelanins

Indole 5,6 quinone Indole-5,6-quinone-2-carboxilic acid

TRP2

dihydroxyindole; DHICA: 5,6-dihydroxyindole-2-carboxylic acid.

Tyrosinase

Cysteinyl-DOPA **Pheomelanins** 

Glutathione orcysteine

DOPA-quinone

Disorders in melanogenesis or in melanocytes can lead to different skin pigmentation pathol‐ ogies. Some disorders are characterized by a loss of skin pigmentation (hypopigmentation) while others are recognized by the presence of dark plaques on the skin formed by an increase of pigmentation (hyperpigmentation).

#### *1.2.1. Hypopigmentation disorders*

Hypopigmentation disorders affect skin pigmentation by the destruction of melanocytes, by preventing development of melanocytes and by inhibiting or retarding melanin production. Vitiligo is characterized by the first mechanism, piebaldism by the second, while oculocuta‐ neous albinism and tinea versicolor are characterized by the third mechanism [27]. These three mechanisms lead to white macules/plaques on the skin because of the lack of melanin pigments.

#### *1.2.1.1. Vitiligo*

Vitiligo is an autoimmune hypopigmentation disorder that affects approximately 1-2 % of the population worldwide. This disease is characterized by the presence of white macules or patches on the skin caused by the loss of functioning epidermal melanocytes [28]. Studies suggest three principal hypotheses on the mechanisms of the melanocyte destruction: auto‐ immunity, neural and toxic hypothesis [29-30]. Autoimmune diseases such as thyroid diseases [31] and diabetes mellitus [32] are often associated with vitiligo. These diseases cause defects in the immune system, which can cause destruction of melanocytes and the loss of pigmenta‐ tion [29]. In addition, antibodies against melanocytes were found in serum of patient, and these can engage the apoptosis of melanocytes when they are present [33]. T cells were also found in perilesional vitiligo plaque biopsies and they are enriched with cytotoxicity against melanocyte antigens [34]. The neural hypothesis is based on the contact of the melanocytes with nerve endings in depigmented skin [35]. Neuropeptides and nerve growth factors such as tumor necrosis factor-α, intercellular adhesion molecule-1 and interferon-γ were found in perilesional skin, which suggest that nerves can have a role in destruction of melanocytes [30]. The toxic hypothesis suggests that the mechanism of natural protection of melanocytes is defective. The melanocytes are unable to eliminate toxic molecules, and these are accumulated in the cells [36]. More than these three mechanisms, the loss of melanocytes can be induced by environmental factors, genetic predispositions [37], apoptosis or metabolic dysfunctions [38]. All these hypotheses are a good way to understand the pathology, but the one single mecha‐ nism of the melanocyte destruction in vitiligo is still unknown.

#### *1.2.1.2. Piebaldism*

Piebaldism is an uncommon hypopigmented disorder characterized by the presence of a congenital white forelock and white macules on the extremities, forehead, frontal scalp and ventral trunk [39]. This pathology is caused by mutations of loss-of-function in the *KIT* gene that encodes for the stem cell growth factor receptor expressed in mastocytes and in melano‐ cytes. When activated, *KIT* is essential to the development of melanocytes and stimulates their proliferation [40]. These mutations prevent the development and the proliferation of melano‐ cytes, thereby causing white macules without melanocytes in skin and in hair.

#### *1.2.1.3. Oculocutaneous albinism*

Oculocutaneous albinism (OCA) is characterized by a disorder in the melanin synthesis in the melanosome due to mutations in specific genes. Tyrosinase or other enzymes essential to the melanogenesis are absent or dysfunctional, resulting in an incapacity in the melanosome to synthesize melanin [41]. People affected by this disease have a complete or a partial loss of pigmentation of the skin, hair and eyes, with the reduced pigmentation in eyes causing a lowering of visual acuity. Four types of albinism exist, all characterized by mutation in a different gene (Table 2). The most severe type is OCA1A, which is characterized by a complete loss of hair and skin pigmentation, while eyes are light blue almost pink. People affected by OCA1B can develop pigmentation on skin, hair and eyes, but they have a characteristic temperature-sensitive pigmentation. Hairs on hands and feet can be pigmented, while body hairs stay depigmented. The most common type worldwide is the OCA2 characterized by various amount of cutaneous pigment and better vision than OCA1. OCA2 and OCA4 have the same clinical characteristics, but differ in the responsible gene. People affected by OCA3 have characteristic red hair and reddish brown skin [42].

#### *1.2.1.4. Tinea versicolor*

Tinea versicolor is a common pigmentation disorder that can be characterized by round shaped hypopigmented and hyperpigmented macules on the face, trunk and arms. These macules are caused by the fungal infection, *Malassezia*, which is a genus normally found in the skin flora [43]. Several factors play a role in the transformation of the benign form of the fungi to the parasitic form. Fatty skin, exposure to sunlight, genetic predispositions, malnutrition and corticosteroids can lead to development of lesions [44]. This lipophilic fungus metabolizes various fatty acids and releases, as one of the metabolites, azelaic acid. This acid acts as an inhibitor of tyrosinase, blocking the transformation of tyrosine in melanin pigment, resulting in hypopigmented macules on the skin. Tinea versicolor is often found in young adults because their sebaceous glands are very active due to the action for sex hormones [45]. The mechanism of hyperpigmented macules is not as well-known as the previous mechanism. Some studies demonstrate that melanosomes are larger in hyperpigmented macules than melanosomes in normal skin and in white macules, but the cause of these enlarged melanosomes is still unknown [14, 45-46].

#### *1.2.2. Hyperpigmentation disorders*

Hyperpigmentation disorders are characterized by darker skin that can be caused by an increase of melanin synthesis or an increase of the melanocytes in the epidermis. "Café-aulait" macules, Addison's disease and postinflammatory hyperpigmentation are characterized by an increased production of melanin, while melanoma is the result of the two causes.


**Table 2.** Gene responsible of oculocutaneous albinism (OCA) different types. TRP1: Tyrosinase-related protein 1

#### *1.2.2.1. "Café-au-lait" macules*

cytes. When activated, *KIT* is essential to the development of melanocytes and stimulates their proliferation [40]. These mutations prevent the development and the proliferation of melano‐

Oculocutaneous albinism (OCA) is characterized by a disorder in the melanin synthesis in the melanosome due to mutations in specific genes. Tyrosinase or other enzymes essential to the melanogenesis are absent or dysfunctional, resulting in an incapacity in the melanosome to synthesize melanin [41]. People affected by this disease have a complete or a partial loss of pigmentation of the skin, hair and eyes, with the reduced pigmentation in eyes causing a lowering of visual acuity. Four types of albinism exist, all characterized by mutation in a different gene (Table 2). The most severe type is OCA1A, which is characterized by a complete loss of hair and skin pigmentation, while eyes are light blue almost pink. People affected by OCA1B can develop pigmentation on skin, hair and eyes, but they have a characteristic temperature-sensitive pigmentation. Hairs on hands and feet can be pigmented, while body hairs stay depigmented. The most common type worldwide is the OCA2 characterized by various amount of cutaneous pigment and better vision than OCA1. OCA2 and OCA4 have the same clinical characteristics, but differ in the responsible gene. People affected by OCA3

Tinea versicolor is a common pigmentation disorder that can be characterized by round shaped hypopigmented and hyperpigmented macules on the face, trunk and arms. These macules are caused by the fungal infection, *Malassezia*, which is a genus normally found in the skin flora [43]. Several factors play a role in the transformation of the benign form of the fungi to the parasitic form. Fatty skin, exposure to sunlight, genetic predispositions, malnutrition and corticosteroids can lead to development of lesions [44]. This lipophilic fungus metabolizes various fatty acids and releases, as one of the metabolites, azelaic acid. This acid acts as an inhibitor of tyrosinase, blocking the transformation of tyrosine in melanin pigment, resulting in hypopigmented macules on the skin. Tinea versicolor is often found in young adults because their sebaceous glands are very active due to the action for sex hormones [45]. The mechanism of hyperpigmented macules is not as well-known as the previous mechanism. Some studies demonstrate that melanosomes are larger in hyperpigmented macules than melanosomes in normal skin and in white macules, but the cause of these enlarged melanosomes is still

Hyperpigmentation disorders are characterized by darker skin that can be caused by an increase of melanin synthesis or an increase of the melanocytes in the epidermis. "Café-aulait" macules, Addison's disease and postinflammatory hyperpigmentation are characterized by an increased production of melanin, while melanoma is the result of the two causes.

cytes, thereby causing white macules without melanocytes in skin and in hair.

have characteristic red hair and reddish brown skin [42].

*1.2.1.3. Oculocutaneous albinism*

764 Regenerative Medicine and Tissue Engineering

*1.2.1.4. Tinea versicolor*

unknown [14, 45-46].

*1.2.2. Hyperpigmentation disorders*

"Café-au-lait" macules are characterized by light to dark brown spots of 1 to 20 cm on the skin that can be of a congenital origin, or appear during life [47]. These spots are often the first sign for the diagnosis of type 1 neurofribromatosis, a disorder caused by mutations in the *NF1* gene, and which can lead to benign and malignant tumors of the peripheral nerve sheath [48]. "Caféau-lait" macules are caused by an increase of melanin in melanocytes and the presence of larger melanosomes in keratinocytes, but the mechanism is still not well-known [49].

#### *1.2.2.2. Malignant melanoma*

Malignant melanoma is one of the most severe skin cancers affecting both men and women. It begins in melanocytes which have been mutated and proliferates to form an irregular naevus, a dark pigmented spot on the skin. In several cases, melanoma begins by forming a normal mole, which is grows increasingly and becomes a metastatic melanoma [50]. Some factors can affect the proliferation of the melanocytes such as genetic factors [51], environmental factors [50], spontaneous mutations [52] and endocrine factors [53]. The most important factor playing a role in this cancer is ultraviolet radiation exposure. UVR cause damages to DNA, the cell usually being able to repair this by the transcription of one of the tumor-suppressor genes, for instance, *p53*. The protein produced by *p53* genes stops the cycle cell, preventing the repro‐ duction of DNA mutations. When there are mutations in the *p53* gene, the cell cycle can not be stopped and mutations in DNA are reproduced and accumulated in the cell that will lead to a hyperproliferation of melanocytes and a melanoma [54]. Other genes such *GADD45*, *PTCH*, *p16*, and oncogenes such as *Bcl-2*, *ras*, *c-fos* can be involved in the pathway of UVinduced melanoma [55].

#### *1.2.2.3. Postinflammatory hyperpigmentation*

Postinflammatory hyperpigmentation occurs after cutaneous inflammation or injury and causes dark plaques on skin. It can affect all types of skin, but dark-skinned people are mostly affected, especially after acne [56]. Hyperpigmented plaques are caused by an overproduction of melanin or an irregular distribution of melanin in the epidermis [57]. The exact mechanism is not well-known, but it has been shown that cytokines, chemokines, inflammatory mediators such as leukotrienes, prostaglandins E2 and D2, thromboxane-2, interleukin IL-1 and IL-6, TNF-α and some others can stimulate melanocyte activity and promote the production of melanin [58].

#### *1.2.2.4. Addison's disease*

Addison's disease, also called adrenal cortical insufficiency, is a rare endocrinal disorder that in more than 50 % of cases is caused by an autoimmune disease. The adrenal glands can not produce enough steroid hormones, resulting in a deficiency in corticosteroids [59]. One of the first indicator symptoms of this disorder is the development of a diffuse hyperpigmentation of the skin (DHP). DHP is caused by the increase of adrenal corticotrophic hormone (ACTH) in the circulation, which has the same precursor molecule to α-MSH, the melanocytesstimulate hormone. Considering that ACTH has approximately the same composition as α-MSH, they will have the same function in the organism: stimulate melanin production [60]. This production of melanin gives people affected by Addison's disease a brown skin, intensi‐ fied at the sites that are exposed to light and pressure, in the skin folds, lines of the hands, nipples and areas of scarring [59].

#### **1.3. Available treatments**

#### *1.3.1. Cosmetic treatments*

Make up, topical dyes and tanning cream are frequently used to cover up undesirable plaques caused by different pigmentation diseases. Cosmetics treatments are practiced to improve the quality of live for young people that can not undergo surgeries because it is not recommended before adulthood. In vitiligo and in piebaldism, dihydroxyacetone (DHA), the browning ingredient in tanning formulations, can be used to camouflage depigmented lesions. DHA polymerizes amino acid of the skin creating pigmentation similar to UV tanning and covering the depigmented plaques of vitiligo and piebaldism patients [61]. However, no melanin pigment is produced and DHA is much less protective against UV than melanin [62]. Some other tanning products can be useful for people affected by a hypopigmentation disorder, while for the hyperpigmentation disorders, patients may use cosmetics such as make-up to cover up their lesions. In postinflammatory hyperpigmentation, scars of acne are frequently concealed with makeup and allow affected people to have a better quality of life [56].

#### *1.3.2. Therapeutic treatment*

#### *1.3.2.1. Hypopigmentation disorders*

Therapeutic treatments, unlike cosmetic treatments, are durable and usually treat the disease. For hypopigmentation disorders, treatment objectives are to increase the production of melanin and the quantity of melanocytes. In vitiligo, the most popular treatment is psoralen-UVA phototherapy (PUVA). This treatment uses the extract of plants such as 8-methoxypsor‐ alen (8-MOP), 5-methoxypsoralen (5-MOP), and a synthetic compound, trisoralen (TMP). These compounds can be used orally or in topical agents by patients, after which, they have to be exposed to sunlight or UVA radiation [36]. PUVA affects skin by increasing the number and the activity of melanocytes in the epidermis resulting in an augmentation of the pigmen‐ tation [63]. Another attractive treatment for vitiligo is immunomodulators. It is suggested that, in this disease, T cells play a role in destruction of melanocytes, and researchers are trying to find immunomodulators that will inhibit them. Cyclosporine is one of them, and prevents the activation of T cells by inactivation of the calcineurin, which is a regulate transcription factor of T cells [64]. Levamisole is another immunomodulators that has been studied for vitiligo treatment, and its sound effectiveness has been demonstrated [65]. The mechanism of action of this compound is not well-known, but no side effect was reported. Vitiligo and piebaldism can be treated with surgeries such as suction blister grafting [36, 66], noncultured melanocytes transplantation [67], cultured epidermis grafting [68] and autologous minigrafting [30]. In tinea versicolor, considering that the disease is caused by a fungus, the principal treatments are topical or oral antifungal agents. Nonspecific topical antifungal agents exist that do not directly affect the fungus, and specific topical antifungal agents that specifically affect the fungus. The most popular nonspecific agents are selenium sulfide and benzol peroxide which chemically remove the infected tissue and prevent a recurrence. Azoles, terbinafine and ciclopiroxolamine are some groups of drugs that are frequently used as specific topical agents to directly attack the fungus [69]. Most of these agents can be taken orally as specific topical agents, and are more effective and simpler for the patient [43]. For oculocutaneous albinism, unfortunately, no treatments are reported to be effective for repigmentation of affected people.

#### *1.3.2.2. Hyperpigmentation disorders*

*1.2.2.4. Addison's disease*

766 Regenerative Medicine and Tissue Engineering

nipples and areas of scarring [59].

**1.3. Available treatments**

*1.3.1. Cosmetic treatments*

*1.3.2. Therapeutic treatment*

*1.3.2.1. Hypopigmentation disorders*

Addison's disease, also called adrenal cortical insufficiency, is a rare endocrinal disorder that in more than 50 % of cases is caused by an autoimmune disease. The adrenal glands can not produce enough steroid hormones, resulting in a deficiency in corticosteroids [59]. One of the first indicator symptoms of this disorder is the development of a diffuse hyperpigmentation of the skin (DHP). DHP is caused by the increase of adrenal corticotrophic hormone (ACTH) in the circulation, which has the same precursor molecule to α-MSH, the melanocytesstimulate hormone. Considering that ACTH has approximately the same composition as α-MSH, they will have the same function in the organism: stimulate melanin production [60]. This production of melanin gives people affected by Addison's disease a brown skin, intensi‐ fied at the sites that are exposed to light and pressure, in the skin folds, lines of the hands,

Make up, topical dyes and tanning cream are frequently used to cover up undesirable plaques caused by different pigmentation diseases. Cosmetics treatments are practiced to improve the quality of live for young people that can not undergo surgeries because it is not recommended before adulthood. In vitiligo and in piebaldism, dihydroxyacetone (DHA), the browning ingredient in tanning formulations, can be used to camouflage depigmented lesions. DHA polymerizes amino acid of the skin creating pigmentation similar to UV tanning and covering the depigmented plaques of vitiligo and piebaldism patients [61]. However, no melanin pigment is produced and DHA is much less protective against UV than melanin [62]. Some other tanning products can be useful for people affected by a hypopigmentation disorder, while for the hyperpigmentation disorders, patients may use cosmetics such as make-up to cover up their lesions. In postinflammatory hyperpigmentation, scars of acne are frequently

concealed with makeup and allow affected people to have a better quality of life [56].

Therapeutic treatments, unlike cosmetic treatments, are durable and usually treat the disease. For hypopigmentation disorders, treatment objectives are to increase the production of melanin and the quantity of melanocytes. In vitiligo, the most popular treatment is psoralen-UVA phototherapy (PUVA). This treatment uses the extract of plants such as 8-methoxypsor‐ alen (8-MOP), 5-methoxypsoralen (5-MOP), and a synthetic compound, trisoralen (TMP). These compounds can be used orally or in topical agents by patients, after which, they have to be exposed to sunlight or UVA radiation [36]. PUVA affects skin by increasing the number and the activity of melanocytes in the epidermis resulting in an augmentation of the pigmen‐ tation [63]. Another attractive treatment for vitiligo is immunomodulators. It is suggested that, in this disease, T cells play a role in destruction of melanocytes, and researchers are trying to In hyperpigmentation disorders, therapeutic treatments have to diminish the melanin production and the quantity of melanocytes. "Café-au-lait" macules are mainly treated with lasers. These lasers must emit a specific wavelength that will be well-absorbed by the chro‐ mophore being treated. In this disease, the referred chromophore is the melanin that has a well-absorbance at 694 nm [70]. Melanin pigment absorption decreases when the wavelength of the laser increases, and thus in this treatment, it is important to choose the appropriate wavelength [71]. For malignant melanoma, several treatments are available, but research for more effective treatments still continue. Currently, the main treatment is the excision of the malignant melanoma, with excision of a large region around the site to make sure that no cancer cell remains. If there are metastases in many other organs, surgery can rarely treat it. In these cases, patients resort to chemotherapy, using drugs which will kill cancer cells by passing into the bloodstream. If the melanoma is recurrent, patient will undergo radiation therapy, high energy rays that cause damage to cancer cells and inhibit their growth, prevent‐ ing the spread of other malignant melanomas. Immunotherapy is also used for the treatment of this cancer. This therapy consists of strengthening the immune system of the patient so that he can fight against cancer cells. Cytokines such as interpheron-α, interleukin-2 and TNF can be used to stimulate the patient's immunity [72-73]. Unlike the previous two diseases, postinflammatory hyperpigmentation is principally treated with the utilisation of medications such as hydroquinone, mequinol, retinoids, azelaic acid and ascorbic acid [56]. Hydroquinone, azelaic acid and mequinol all affect tyrosinase to inhibit the melanin production, but not in the same way. Hydroquinone and azelaic acid will interfere with tyrosinase, while mequinol acts like a competitive substrate of tyrosinase [74]. Retinoids such as tretinoin and tazatorene help the penetration of other medications through the skin barrier by causing skin irritation and inducing the apoptosis of mature melanocytes [75]. Ascorbic acid suppresses the melanin production by reducing the formation of quinones, creating a lack in the melanogenesis process [76]. However, postinflammatory hyperpigmentation can be treated by a peeling surgery, a technique that uses chemical products for destruction of a part of the dermis and/or the epidermis [77]. Finally, diffuse hyperpigmentation in Addison's disease is usually treated with mineralocorticoid and glucocorticoid [78]. These two corticosteroids will compensate for the lack of corticosteroids, reduce the production of ACTH, and thus, reduce the production of melanin pigments. Considering that it is a rare disease, treatments are not very abundant. The development of pigmented skin models could be useful for studying unknown mechanisms involved in these disorders, and for developing more relevant treatments with few side effects.
