A Novel Method for Visualizing Melanosome and Melanin Distribution in Human Skin Tissues
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Abstract:
Melanin incorporated into keratinocytes plays an important role in photoprotection; however, abnormal melanin accumulation causes hyperpigmentary disorders. To understand the mechanism behind the accumulation of excess melanin in the skin, it is essential to clarify the spatial distribution of melanosomes or melanin in the epidermis. Although several markers have been used to detect melanosomes or melanin, no suitable markers to determine the precise localization of melanin in the epidermis have been reported. In this study, we showed that melanocore-interacting Kif1c-tail (M-INK), a recently developed fluorescent probe for visualizing mature melanosomes, binds to purified melanin in vitro, and applied it for detecting melanin in human skin tissues. Frozen skin sections from different phototypes were co-stained for the hemagglutinin (HA)-tagged M-INK probe and markers of melanocytes or keratinocytes, and a wide distribution of melanin was observed in the epidermis. Analysis of the different skin phototypes indicated that the fluorescent signals of HA-M-INK correlated well with skin color. The reconstruction of three-dimensional images of epidermal sheets enabled us to observe the spatial distribution of melanin in the epidermis. Thus, the HA-M-INK probe is an ideal tool to individually visualize melanin (or melanosome) distribution in melanocytes and in keratinocytes in skin tissues.Keywords:
Melanosome
Epidermis (zoology)
Human skin
Melanocyte
Normal skin pigmentation is a complex process that, in the epidermis as in the hair follicles, begins with the synthesis of melanin within melanosomes in the melanocytes, followed by melanosome transfer to neighboring basal and suprabasal keratinocytes. In basal cells, melanin granules are translocated to the upper pole of the nucleus, forming a melanin cap that protect DNA from UV rays. Melanin granules are eventually degraded as the keratinocyte undergoes terminal differentiation. In (...)
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Melanocyte
Epidermis (zoology)
Basal (medicine)
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Melanocyte
Granule (geology)
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Abstract The major source of color in human skin derives from the presence within the epidermis of specialized melanin‐bearing organelles, the melanosomes. Tanning of human skin on exposure to ultraviolet light results from increased amounts of melanin within the epidermis. Melanosomes synthesized by melanocytes are acquired by keratinocytes and transported within them to the epidermal surface. In some cases, the melanosomes are catabolized en route . New information indicates that the multicellular epidermal melanin unit (melanocyte and associated pool of keratinocytes) rather than the melanocyte alone is the focal point for the control of melanin metabolism within mammalian epidermis. Gross human skin color derives from the visual impact of the summed melanin pigmentation of the many epidermal melanin units. In theory, constitutive skin color in man designates the genetically‐determined levels of melanin pigmentation developed in the absence of exposure to solar radiations or other environmental influences; facultative skin color or “tan” characterizes the increases in melanin pigmentation above the constitutive level induced by ultraviolet light. The details of genetic regulation of pigment metabolism within the epidermal melanin units are being clarified. In some mammals at least, the function of epidermal melanin units is significantly influenced by hormones which may be regulated by radiations received through the eyes. Based on an evolutionary history of the human family which exceeds ten million years, it is proposed that melanin pigmentation may have played a number of roles in human adaptations to changing biologic and physical environments.
Melanosome
Melanocyte
Epidermis (zoology)
Human skin
Photobiology
Skin Color
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The presence of melanin macroglobules, and sometimes that of melanosome complexes also, in epidermal melanocytes has been considered a feature of various skin diseases. Opinions differ as to whether these structures can occur in normal skin. We have studied these melanin inclusions in normal Caucasian skin in the entire soma of 116 melanocytes and the occurrence of melanosomes in phagosomes of 77 Langerhans' cells obtained in different seasons. During winter the melanocytes contained few melanosomes but many melanosome complexes and melanin macroglobules. These melanosome inclusions were in 86%, localized in the most basal part of the melanocytes, particularly in the dermal protrusions. It is suggested that these structures can be transferred from epidermal melanocytes to dermal cells and that melanin macroglobules derive from melanosome complexes. Irrespective of the season, most of the Langerhans' cells contained melanosomes in their phagosomes, which suggests a phagocytic capacity of these cells and a role in the elimination of the melanin.
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Melanocyte
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This study elucidates the nature of melanogenesis in B16 and Harding-Passey (HP) mouse melanomas producing melanin and melanosomes of different color and fine structure, i.e., brown-black eumelanosome-like B16 granules and reddish brown pheomelanosome-like HP granules, and compares them with "typical" 3,4-dihydroxyphenylalanine (DOPA) and sepia eumelanins and sepia eumelanosomes. The melanin content of B16 melanosomes was more than three times higher than that of HP melanosomes. The content of free and protein-bound DOPA and 5-S-cysteinyldopa varied greatly in B16, HP, and sepia melanosomes and was unrelated to melanin content. Chemical analysis of the eumelanin: pheomelanin ratio in melanosomes and elemental analysis of isolated melanin showed that B16 and HP melanins are primarily eumelanic, with a higher ratio of pheomelanic component in HP melanin. The spectra of electron spin resonance and IR and X-ray small-angle scattering of B16 and HP melanins were basically similar to those of sepia and DOPA melanins. B16, HP, and DOPA melanins were dissolved in aqueous NH3, while sepia melanin was dissolved to a far lesser extent. It was concluded that both B16 and HP melanomas are primarily involved in eumelanogenesis, although the fine structure of their melanosomes is entirely different, and that the marked color difference in the two melanosomes is related to a difference in the absolute content of eumelanin, the presence of a small amount of pheomelanin, and the mode of chemical bindings of melanin to structural proteins. In contrast to normal skin and hair, melanosome morphogenesis may not directly correspond to melanogenesis type in malignant melanoma.
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Cuttlefish
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Abstract The steady increase in the incidence of cutaneous (skin) malignant melanoma worldwide generates the necessity to understand the key molecular events underlying melanogenesis and melanoma. Melanogenesis has two main stages: immediate pigmentation occurs through the redistribution of pigment‐containing melanosomes to the dendrites of melanocytes, and subsequently to the surrounding keratinocytes, without the need for any new melanin synthesis. The effect is therefore subtle and transient. Delayed and sustained tanning, however, requires (a) an increase in melanocyte number and dendricity, (b) an increase in melanosome number, and (c) an increase in melanin content. This computer‐based model focuses on the sustained eumelanin (black/brown pigment) production through melanocyte‐specific gene expression in response to external stimulus. We find in our model that high levels of melanin can be reached within an hour of stimulation. Furthermore we successfully show metabolic downregulation of pigment synthesis through employing in our simulations an experimentally‐described inhibitor for melanogenic enzymes. We see this model as a starting point for in silico drug screening for skin lightening agents, sun‐tanning agents, and eventually for anti‐melanoma agents that are under development.
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Microphthalmia-associated transcription factor
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The key to diagnosing cases of melanoma, a tumor of melanocytes, is to recognize cytoplasmic pigment called melanin. In most cases this can be done at the light microscopy level; however, in the rarer amelanotic (non-pigmented) melanomas, melanin is not present in detectable amounts. Thus it is necessary to do an ultxastructural investigation to detect melanosomes, the specific organelles of the melanocyte that synthesize melanin. Other non-melanoma cells can also possess melanin by internalization of melanin granules by phagocytosis or passive transfer (e.g. macrophages, keratinocytes) but they lack the premelanosome organelle, the precursor to the fully developed melanosome. In premelanosomes, the internal structures are not obscured by melanin. Thus it is the diagnostic feature of choice for the pathologist. In malignant melanoma, aberrant forms of premelanosomes and melanosomes are more typical than in normal melanocytes., These aberrant forms may not be well recognized. Amelanotic melanomas give us a good opportunity to study these structures. In studying premelanosomes,the investigator must be aware of variations of size, shape, appearance in different planes of sections, and knowledge of the four stages of normal melanosome development (melanogenesis).
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Amelanotic melanoma
Melanocyte
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A primary role of melanin in skin is the prevention of UV-induced nuclear DNA damage to human skin cells, where it serves to screen out harmful UV radiation. Melanin is delivered to keratinocytes in the skin after being excreted as melanosomes from melanocytes. Defects in melanin production in humans can cause diseases, many of which currently lack effective treatments due to their genetic origins (e.g., skin cancer, vitiligo, and albinism). The widespread prevalence of melanin-related diseases and an increasing interest in the performance of various polymeric materials related to melanin necessitates novel synthetic routes for preparing melanin-like materials. In this work, we prepared melanin-like nanoparticles (MelNPs) via spontaneous oxidation of dopamine, as biocompatible, synthetic analogues of naturally occurring melanosomes, and investigated their uptake, transport, distribution, and UV-protective capabilities in human keratinocytes. Critically, we demonstrate that MelNPs are endocytosed, undergo perinuclear aggregation, and form a supranuclear cap, or so-called microparasol in human epidermal keratinocytes (HEKa), mimicking the behavior of natural melananosomes in terms of cellular distribution and the fact that they serve to protect the cells from UV damage.
Melanosome
Vitiligo
Human skin
Biocompatible material
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Melanosome
Human skin
Skin Aging
Skin Color
Epidermis (zoology)
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