Melanosome Transfer Research Articles

A Review on Vyangavis a vis Melasma

Ayurvedais one of the oldest comprehensive health care system worldwide. Ayurvedicscience being ancient and traditional still correlate with day to day medical conditions and their treatment. Melasma being a non communicable and non deteriorated condition is still a mental trauma in human life especially for the younger age group. Melasma is a common acquired condition of symmetrical hyper pigmentation typically occurring on the face with higher prevalence in females and darker skin types. It is is characterized by more or less dark brownish maculae with irregular contour , but clear limits on photo exposed areas especially on the face, forehead, temples and more rarely on the nose, eyelids, chin and upper lips. In Ayurveda, vyanga has been elaborated as one of the kshudra rogas(minor ailments). VYANGA, a type of kshudra Roga, characterized by niruja(painless), shayavvarna mandala(bluish black patches) occurring specially on the face. The clinical features correlate with melasma which is acquired and symmetrical hypermelanosis . Vyangais a disease which belongs toswalpavariety of kshudra Roga. Vayuaggravated by Krodh and ayasa, get associated with pittaand suddenly produces a thin grey coloured circular patch which reaches the face. As per medical science melasma, cutaneous pigmentation is the outcome of two important events, the synthesis of melanin by melanocyte and the transfer of melanosomes to surrounding Keratinocytes. Both modern andayurvedicsciences have considered the use of topical as well asoral medications and their combinations for the treatment of vyanga. In Ayurveda,vyangahas been treated both by antah parimarjanand bahya parimarjan chikitsa. Several ayurvedic text such as Sushruta Samhitaand AshtangaHridayaand Sangrahaetc, have elaborated the pathophysiology and treatment of vyanga, the available references are scattered. So, there is a need of in-depth review and compilation of ayurvedictext and literatures which are effective for the management of vyanga

309 Dynlt3, a novel fundamental regulator of melanosome movement, distribution, acidity and transfer

Skin pigmentation is dependent on a number of cellular processes including melanosome biogenesis, transport, maturation and transfer to keratinocytes. However, how the cells finely control these processes in space and time to ensure proper pigmentation remains unclear. In this work, we have shown that Dynlt3, a component of the cytoplasmic dynein complex, is required for efficient melanosome transport, acidity and transfer. In melanocytes with decreased levels of Dynlt3, pigmented melanosomes undergo a more directional motion, leading to their peripheral location in the cell. Decreased levels of Dynlt3 also result in increased acidity of stage IV, heavily pigmented, melanosomes. Melanosome transfer to neighboring keratinocytes is also decreased upon knockdown of Dynlt3. Finally, the level of Dynlt3 is dependent on β-catenin activity, revealing a novel function of the Wnt/β-catenin signalling pathway during melanocyte and skin pigmentation, by coupling the transport, positioning and acidity of melanosomes required for their transfer.

Melanocytes as emerging key players in niche regulation of limbal epithelial stem cells

PurposeLimbal melanocytes (LMel) represent essential components of the corneal epithelial stem cell niche and are known to protect limbal epithelial stem/progenitor cells (LEPCs) from UV damage by transfer of melanosomes. Here, we explored additional functional roles for LMel in niche homeostasis, immune regulation and angiostasis. MethodsHuman corneoscleral tissues were morphologically analyzed in normal, inflammatory and wound healing conditions. The effects of LMel on LEPCs were analyzed in direct and indirect co-culture models using electron microscopy, immunocytochemistry, qRT-PCR, Western blotting and functional assays; limbal mesenchymal stromal cells and murine embryonic 3T3 fibroblasts served as controls. The immunophenotype of LMel was assessed by flow cytometry before and after interferon-γ stimulation, and their immunomodulatory properties were analyzed by mixed lymphocytes reaction, monocyte adhesion assays and cytometric bead arrays. Their angiostatic effects on human umbilical cord endothelial cells (HUVECs) were evaluated by proliferation, migration, and tube formation assays. ResultsLMel and LEPCs formed structural units in the human limbal stem cell niche in situ, which could be functionally replicated, including melanosome transfer, by co-cultivation in vitro. LMel supported LEPCs during clonal expansion and during epithelial wound healing by stimulating proliferation and migration, and suppressed their differentiation through direct contact and paracrine effects. Under inflammatory conditions, LMel were increased in numbers and upregulated expression of ICAM-1 and MHC II molecules (HLA-DR), but lacked expression of HLA-G, -DP, -DQ and costimulatory molecules CD80 and CD86. They were also found to be potent suppressors of alloreactive T- cell proliferation and cytokine secretion, which largely depended on direct cell-cell interaction. Moreover, the LMel secretome exerted angiostatic activity by inhibiting vascular endothelial cell proliferation and capillary network formation. ConclusionThese findings suggest that LMel are not only professional melanin-producing cells, but exert various non-canonical functions in limbal niche homeostasis by regulating LEPC maintenance, immune responses, and angiostasis. Their potent regulatory, immunomodulatory and anti-angiogenic properties may have important implications for future regenerative cell therapies.

The Ethanol Extract of Musa sapientum Linn. Peel Inhibits Melanogenesis through AKT Signaling Pathway

Hyperpigmentation caused by melanin overproduction can be induced by UV radiation. The quest for effective depigmenting agents continues because many anti-melanin agents have restricted use and/or produce side-effects. The present study was aimed to investigate the inhibitory activity of Musa sapientum Linn. (AA group) peel ethanol extracts (MPE) on α-melanocyte stimulating hormone (α-MSH)-induced melanin production. In addition, the molecular mechanism related to this process was examined in B16F10 mouse melanoma cells. The results indicated that MPE remarkably inhibited melanogenesis in α-MSH-stimulated B16F10 cells. Microphthalmia-associated transcription factor (MITF) and tyrosinase expressions were suppressed by MPE in a concentration-dependent manner. In addition, MPE significantly decreased the expression of melanosome transfer protein markers (Rab27a and Pmel17) in a dose-dependent manner. This study found that the elevated phosphorylation of AKT in the B16F10 cells was diminished by MPE treatment. Furthermore, microtubule-associated protein 1 light chain 3 (LC3)-II and p62 (autophagy markers) were affected after the B16F10 cells were treated with MPE. This study demonstrated that MPE might be an effective agent for anti-melanogenesis through the AKT pathway, subsequently diminishing MITF expression and tyrosinase enzyme family production. The findings indicated that MPE could potentially serve as a depigmenting agent in cosmeceuticals.

Nicotinamide as a Skin Whitener: Evidence and Controversies

Background: Topical nicotinamide (NAM) can reduce excessive melanin deposition in cell culture, by reversibly blocking the transfer of melanosomes from melanocytes to the adjacent keratinocytes. Thus, it has been increasingly used as a whitening agent.
 Objective: To assess the efficacy and safety of topical nicotinamide used for the treatment of melasma and hyperpigmentation.
 Methods: An electronic search for topical nicotinamide was carried out on Pubmed and Medline databases to identify studies that addressed this topic as a whitening agent. And to review the primary and secondary outcomes.
 Results: A significant decrease in hyperpigmentation and increased skin lightness was found with the use of topical nicotinamide, compared with the vehicle In two small sample size clinical studies. Combined regimens including nicotinamide and other ingredients offer more synergistic effects than monotherapy.
 Conclusion: Due to the lack of sufficient evidence, the use of nicotinamide for melasma remains controversial. Extended randomized, double-blind, placebo-controlled trials with long-term follow-up periods are needed to assess the efficacy of nicotinamide as a whitening agent.

Differential diagnosis and management of hyperpigmentation.

There is an increasing recognition of ethnic dermatology to reflect the increase in skin of colour (SOC) populations in the UK. Hyperpigmentary disorder is one of the commonest skin concerns in SOC but there has been limited training available in this field of dermatology. Variations in skin colour are genetically determined by the amount of melanin content, the eumelanin/pheomelanin ratio and the size of melanosomes, but is also influenced by other factors such as hormones and extrinsic factors such as ultraviolet radiation. Hyperpigmentation is a broad term to describe increased pigmentation in the skin, and making a correct diagnosis is an important first step in the successful management of hyperpigmentary disorders. A systematic approach based on the disease pathogenesis (e.g. reactive vs. nonreactive, increased melanin vs. increased number of cells or epidermal vs. dermal pigmentation) aided by a detailed history and clinical examination is the best way to diagnose a hyperpigmentary disorder. Based on its pathogenesis, management can be planned. For epidermal hyperpigmentation caused by increased melanin, topical skin-lightening agents targeting inhibition of tyrosinase or melanosome transfer and promotion of keratinocyte turnover can be used. Hydroquinone-containing cream is the gold-standard treatment for epidermal hyperpigmentation. Alternative treatments include laser toning or chemical peels. However, increased dermal pigmentation is more challenging to target with topical treatments. If hyperpigmentation is due to increased numbers of melanocytes or keratinocytes, high-fluence laser is the most appropriate treatment method.

Synthesis and characterization of gold nanoparticles biosynthesised from Aspalathus linearis (Burm.f.) R.Dahlgren For progressive macular hypomelanosis

IntroductionThe study investigated a natural solution for the hypopigmentary disorder, progressive macular hypomelanosis (PMH). The aim was to determine whether gold nanoparticles synthesized from Aspalathus linearis (Burm.f.) R.Dahlgren could be effective for PMH. MethodsGold nanoparticles (ALAuNPs) were synthesized using the ethanolic extract of A. linearis (ALEtOH) and tested, along with the extract for its regulatory effect of melanogenesis in human melanocytes and its antibacterial activity against Cutibacterium acnes (ATCC 6919 strain). Melanosome transfer was determined in a co-culture of normal human melanocytes and keratinocytes and was quantified using flow cytometry. ResultsThe ALAuNPstab (AuNPs stabilized with gum arabic) and ALAuNPnon-stab (non-stabilized) exhibited significantly (P < 0.001) higher antibacterial activity against C. acnes with 50 % inhibition at a concentration of 66.05 ± 1.10 μg/mL and 68.12 ± 1.05 μg/mL, respectively, as compared to that of ALEtOH (271.20 ± 2.32 μg/mL). The ALEtOH exhibited 50 % reduction in cell proliferation (IC50 value) in human melanocytes at 345.5 ± 2.47 μg/mL, whilst ALAuNPstab and ALAuNPnon-stab exhibited an IC50 value of 67.51 ± 1.12 and 69.63 ± 1.07 μg/mL, respectively. The ALEtOH and ALAuNPstab tested at a concentration of 62.5 μg/mL, exhibited a significant increase (P < 0.001) in the total number of melanin present in human melanocytes compared to the untreated (control) cells. The cells treated with ALEtOH and ALAuNPstab led to a significant (P < 0.001) increase in the number of melanosomes transferred as compared to the untreated cells. ConclusionThis study confirmed that A. linearis and its biosynthesised gold nanoparticles stimulated melanin synthesis.

A role for Dynlt3 in melanosome movement, distribution, acidity and transfer

Skin pigmentation is dependent on cellular processes including melanosome biogenesis, transport, maturation and transfer to keratinocytes. However, how the cells finely control these processes in space and time to ensure proper pigmentation remains unclear. Here, we show that a component of the cytoplasmic dynein complex, Dynlt3, is required for efficient melanosome transport, acidity and transfer. In Mus musculus melanocytes with decreased levels of Dynlt3, pigmented melanosomes undergo a more directional motion, leading to their peripheral location in the cell. Stage IV melanosomes are more acidic, but still heavily pigmented, resulting in a less efficient melanosome transfer. Finally, the level of Dynlt3 is dependent on β-catenin activity, revealing a function of the Wnt/β-catenin signalling pathway during melanocyte and skin pigmentation, by coupling the transport, positioning and acidity of melanosomes required for their transfer.

Whitening effect of novel peptide mixture by regulating melanosome biogenesis, transfer and degradation.

Peptides are short chain of amino acids linked by peptide bonds. They are widely used as effective and biocompatible active ingredients in cosmetic industry. In this study, we developed novel peptide mixture and identified its anti-pigmentation effect on melanocytes and keratinocytes. Our results revealed that peptide mixture inhibited melanosome biogenesis through the regulation of microphthalmia-associated transcription factor, a key factor of melanogenesis in melanocytes. And we observed that peptide mixture inhibited melanosome uptake through the reduction of protease-activated receptor 2, a phagocytosis-related receptor in keratinocytes. Furthermore, peptide mixture activated autophagy system resulting in degradation of transferred melanosomes in keratinocytes. The anti-pigmentation effect of multi-targeting peptide mixture was assessed in a human skin equivalent model (MelanoDerm). Melanin contents in epidermal layer were significantly decreased by topical treatment of peptide mixture, suggesting that it can be applied as a novel cosmetics material having a whitening function.

Dowling-Degos disease: a review.

Dowling-Degos disease is a rare autosomal dominant genodermatosis. It is characterized by acquired reticulate hyperpigmentation over the flexures, comedone-like follicular papules, and pitted perioral scars that usually develop during adulthood. Mutations in genes affecting melanosome transfer, and melanocyte and keratinocyte differentiation have been implicated in the pathogenesis of this disease. These genes include KRT5, POFUT1, POGLUT1 and, most recently, PSENEN. Dowling-Degos disease can be found in isolation or with other associated findings, most notably hidradenitis suppurativa. This condition belongs to a spectrum of conditions that all result in reticulate hyperpigmentation that at times are hard to distinguish from each other. The most closely linked entity is Galli-Galli, which is clinically indistinguishable from Dowling-Degos disease and can only be distinguished by the presence of acantholysis on microscopy. Unfortunately, Dowling-Degos disease is generally progressive and recalcitrant to treatment.

Age-related graying of the hair — a brief summary of potential mechanisms

Graying of the hair is one of the most eye-catching phenotypic changes related to the chronological aging. During the last decades, scientists have engaged in research that has increased our understanding of different mechanisms of aging of a hair follicle, however many aspects of this process remain unclear. Progressive hypopigmentation of the hair shaft has been associated with decrease in number of melanocytes and tyrosinase hypoactivity in the hair bulb along with the depletion of melanocyte stem cells (MSCs) in the bulge area. Pathogenesis of graying may involve oxidative damage and incompetent MSCs maintenance. Moreover, other factors such as defective melanosomal transfer as well as insufficient neuroendocrine stimulation of MSCs and melanogenesis are hypothesized to play an important role.

Rab GTPases: Key players in melanosome biogenesis, transport, and transfer.

Melanosomes are specialized intracellular organelles that produce and store melanin pigments in melanocytes, which are present in several mammalian tissues and organs, including the skin, hair, and eyes. Melanosomes form and mature stepwise (stages I-IV) in melanocytes and then are transported toward the plasma membrane along the cytoskeleton. They are subsequently transferred to neighboring keratinocytes by a largely unknown mechanism, and incorporated melanosomes are transported to the perinuclear region of the keratinocytes where they form melanin caps. Melanocytes also extend several dendrites that facilitate the efficient transfer of the melanosomes to the keratinocytes. Since the melanosome biogenesis, transport, and transfer steps require multiple membrane trafficking processes, Rab GTPases that are conserved key regulators of membrane traffic in all eukaryotes are crucial for skin and hair pigmentation. Dysfunctions of two Rab isoforms, Rab27A and Rab38, are known to cause a hypopigmentation phenotype in human type 2 Griscelli syndrome patients and in chocolate mice (related to Hermansky-Pudlak syndrome), respectively. In this review article, I review the literature on the functions of each Rab isoform and its upstream and downstream regulators in mammalian melanocytes and keratinocytes.

Three-dimensional structure analysis of melanocytes and keratinocytes in senile lentigo.

Senile lentigo or age spots are hyperpigmented macules of skin that commonly develop following long-term exposure to ultraviolet radiation. This condition is caused by accumulation of large numbers of melanosomes (melanin granules) produced by melanocytes within neighboring keratinocytes. However, there is still no consensus regarding the melanosome transfer mechanism in senile lentigo. To date, most pathohistological studies of skin have been two-dimensional and do not provide detailed data on the complex interactions of the melanocyte-keratinocyte network involved in melanosome transfer. We performed a three-dimensional reconstruction of the epidermal microstructure in senile lentigo using three different microscopic modalities to visualize the topological melanocyte-keratinocyte relationship and melanosome distribution. Confocal laser microscopy images showed that melanocyte dendritic processes are more frequently branched and elongated in senile lentigo skin than in normal skin. Serial transmission electron micrographs showed that dendritic processes extend into intercellular spaces between keratinocytes. Focused ion beam-scanning electron micrographs showed that dendritic processes in senile lentigo encircle adjacent keratinocytes and accumulate large numbers of melanosomes. Moreover, melanosomes transferred to keratinocytes are present not only in the supranuclear area but throughout the perinuclear area except on the basal side. The use of these different microscopic methods helped to elucidate the three-dimensional morphology and topology of melanocytes and keratinocytes in senile lentigo. We show that the localization of melanosomes in dendritic processes to the region encircling recipient keratinocytes contributes to efficient melanosome transfer in senile lentigo.

The biology of human hair greying.

Hair greying (canities) is one of the earliest, most visible ageing-associated phenomena, whose modulation by genetic, psychoemotional, oxidative, senescence-associated, metabolic and nutritional factors has long attracted skin biologists, dermatologists, and industry. Greying is of profound psychological and commercial relevance in increasingly ageing populations. In addition, the onset and perpetuation of defective melanin production in the human anagen hair follicle pigmentary unit (HFPU) provides a superb model for interrogating the molecular mechanisms of ageing in a complex human mini-organ, and greying-associated defects in bulge melanocyte stem cells (MSCs) represent an intriguing system of neural crest-derived stem cell senescence. Here, we emphasize that human greying invariably begins with the gradual decline in melanogenesis, including reduced tyrosinase activity, defective melanosome transfer and apoptosis of HFPU melanocytes, and is thus a primary event of the anagen hair bulb, not the bulge. Eventually, the bulge MSC pool becomes depleted as well, at which stage greying becomes largely irreversible. There is still no universally accepted model of human hair greying, and the extent of genetic contributions to greying remains unclear. However, oxidative damage likely is a crucial driver of greying via its disruption of HFPU melanocyte survival, MSC maintenance, and of the enzymatic apparatus of melanogenesis itself. While neuroendocrine factors [e.g. alpha melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH), ß-endorphin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH)], and micropthalmia-associated transcription factor (MITF) are well-known regulators of human hair follicle melanocytes and melanogenesis, how exactly these and other factors [e.g. thyroid hormones, hepatocyte growth factor (HGF), P-cadherin, peripheral clock activity] modulate greying requires more detailed study. Other important open questions include how HFPU melanocytes age intrinsically, how psychoemotional stress impacts this process, and how current insights into the gerontobiology of the human HFPU can best be translated into retardation or reversal of greying.

Recent advances in understanding the molecular basis of melanogenesis in melanocytes.

Melanin pigments are responsible for human skin and hair color, and they protect the body from harmful ultraviolet light. The black and brown melanin pigments are synthesized in specialized lysosome-related organelles called melanosomes in melanocytes. Mature melanosomes are transported within melanocytes and transferred to adjacent keratinocytes, which constitute the principal part of human skin. The melanosomes are then deposited inside the keratinocytes and darken the skin (a process called tanning). Owing to their dark color, melanosomes can be seen easily with an ordinary light microscope, and melanosome research dates back approximately 150 years; since then, biochemical studies aimed at isolating and purifying melanosomes have been conducted. Moreover, in the last two decades, hundreds of molecules involved in regulating melanosomal functions have been identified by analyses of the genes of coat-color mutant animals and patients with genetic diseases characterized by pigment abnormalities, such as hypopigmentation. In recent years, dynamic analyses by more precise microscopic observations have revealed specific functions of a variety of molecules involved in melanogenesis. This review article focuses on the latest findings with regard to the steps (or mechanisms) involved in melanosome formation and transport of mature melanosomes within epidermal melanocytes. Finally, we will touch on current topics in melanosome research, particularly on the "melanosome transfer" and "post-transfer" steps, and discuss future directions in pigment research.

PD-L1 produced by HaCaT cells under polyinosinic-polycytidylic acid stimulation inhibits melanin production by B16F10 cells.

Skin forms a physical barrier that protects the body against outside agents. The deepest layer of the skin, the stratum basale, contains two cell types: agent-sensing keratinocytes, and melanin-producing melanocytes. Keratinocytes can sense both harmless commensal organisms and harmful pathogens via Toll-like receptors (TLRs), and keratinocytes subsequently drive immune responses. Activation of TLR3 is required for barrier repair because it stimulates essential genes, including tight junction genes, and inflammatory cytokines. Within the basal layer of the skin, resident melanocytes use their dendritic processes to connect with approximately 30–40 neighboring keratinocytes. Most studies have focused on the transfer of melanin-synthesizing melanosomes from melanocytes to keratinocytes, but the potential regulation of melanogenesis by soluble factor(s) produced by keratinocytes remains to be explored. Studying such regulation in vivo is challenging because of the keratinocyte:melanocyte ratio in the epidermis and the location of the cells within the skin. Therefore, in this study, we investigated whether keratinocytes affected melanocyte melanogenesis in vitro under normal or inflammatory conditions. We found that polyinosinic-polycytidylic acid [poly(I:C)] stimulation induced PD-L1 secretion from HaCaT cells and that poly(I:C)-induced PD-L1 inhibited melanin production by B16F10 cells. These data provide key evidence that keratinocytes can alter melanocyte melanogenesis via the production of soluble factors under inflammatory conditions.

Slide-free clinical imaging of melanin with absolute quantities using label-free third-harmonic-generation enhancement-ratio microscopy.

The capability to image the 3D distribution of melanin in human skin in vivo with absolute quantities and microscopic details will not only enable noninvasive histopathological diagnosis of melanin-related cutaneous disorders, but also make long term treatment assessment possible. In this paper, we demonstrate clinical in vivo imaging of the melanin distribution in human skin with absolute quantities on mass density and with microscopic details by using label-free third-harmonic-generation (THG) enhancement-ratio microscopy. As the dominant absorber in skin, melanin provides the strongest THG nonlinearity in human skin due to resonance enhancement. We show that the THG-enhancement-ratio (erTHG) parameter can be calibrated in vivo and can indicate the melanin mass density. With an unprecedented clinical imaging resolution, our study revealed erTHG-microscopy's unique capability for long-term treatment assessment and direct clinical observation of melanin's micro-distribution to shed light into the unknown pathway and regulation mechanism of melanosome transfer and translocation.

Saccharomyces cerevisiae as a skin physiology, pathology, and treatment model

Saccharomyces cerevisiae serves as a useful model in experimental biology. Within dermatology research, several studies have examined this organism's role in skin physiology, pathology, and treatment. Saccharomyces cerevisiae has been used to explore the mechanisms of melanogenesis as its extract inhibits key enzymes involved in melanogenesis and melanosome transfer. Additionally, the lack of probiotic intestinal Saccharomyces cerevisiae has been associated with psoriasis, potentially related to the anti-inflammatory effects of the yeast. Furthermore, antibodies against Saccharomyces cerevisiae have been observed in skin conditions, including atopic dermatitis. Saccharomyces cerevisiae may even cause skin infections, such as septic emboli in a patient with acute myelogenous leukemia. Lastly, Saccharomyces cerevisiae has potential use in vaccine development against melanoma and is utilized to study various treatment modalities such as zinc pyrithione, an ingredient often used in anti-dandruff shampoo.

Future therapies in melasma: What lies ahead?

Melasma is a common, acquired, symmetrical hypermelanosis. It negatively impacts the patient's quality of life and responds poorly to treatment. Although earlier classified as epidermal and dermal, melasma is now thought to be a complex interaction between epidermal melanocytes, keratinocytes, dermal fibroblasts, mast cells, and vascular endothelial cells. Factors influencing melasma may include inflammation, reactive oxygen species, ultraviolet radiation, genetic factors, and hormones. With a better understanding of the pathogenesis of melasma and the realization that targeting melanin synthesis alone is not very effective, treatments focussing on newly implicated factors have been developed. These include agents targeting hyperactive melanocytes, melanosomal transfer to keratinocytes, defective skin barrier, the mast cells, vasculature, and estrogen receptors as well as drugs with anti-inflammatory and antioxidant activity. Many of these newer agents are botanicals with multimodal mechanisms of action that offer a better safety profile when compared with the conventional drugs. There has also been a focus on oral agents such as tranexamic acid, flutamide, and ascorbic acid. It has been suggested that the "triple therapy of the future" may be a combination of hydroquinone, an antiestrogen and a vascular endothelial growth factor inhibitor, as the "ideal" skin-lightening agent.

Epidermal keratin 5 expression and distribution is under dermal influence.

Human skin melanin pigmentation is regulated by systemic and local factors. According to the type of melanin produced by melanocytes, the transfer and degradation of melanosomes differ, thus accounting for most variations between ethnicities. We made the surprising observation that in a drastically changed environment, white and black phenotypes are reversible since Caucasian skin grafted onto nude mice can become black with all black phenotypic characteristics. Black xenografts differed essentially from other grafts by the levels of epidermal FGF-2 and keratin 5. In vitro analysis confirmed that FGF-2 directly regulates keratin 5. Interestingly, this phenomenon may be involved in human pathology. Keratin 5 mutations in Dowling-Degos Disease (DDD) have already been associated with the pheomelanosome-eumelanosome transition. In a DDD patient, keratin 5 was expressed in the basal and spinous layers, as observed in black xenografts. Furthermore, in a common age-related hyperpigmentation disorder like senile lentigo (SL), keratin 5 distribution is also altered. In conclusion, modulation of keratin 5 expression and distribution either due to mutations or factors may account for the development of pigmentary disorders.