Reconstructed human pigmented skin/epidermis models achieve epidermal pigmentation through melanocore transfer (original) (raw)
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Melanin Transfer in the Epidermis: The Pursuit of Skin Pigmentation Control Mechanisms
International Journal of Molecular Sciences, 2021
The mechanisms by which the pigment melanin is transferred from melanocytes and processed within keratinocytes to achieve skin pigmentation remain ill-characterized. Nevertheless, several models have emerged in the past decades to explain the transfer process. Here, we review the proposed models for melanin transfer in the skin epidermis, the available evidence supporting each one, and the recent observations in favor of the exo/phagocytosis and shed vesicles models. In order to reconcile the transfer models, we propose that different mechanisms could co-exist to sustain skin pigmentation under different conditions. We also discuss the limited knowledge about melanin processing within keratinocytes. Finally, we pinpoint new questions that ought to be addressed to solve the long-lasting quest for the understanding of how basal skin pigmentation is controlled. This knowledge will allow the emergence of new strategies to treat pigmentary disorders that cause a significant socio-economi...
Melanin Transfer and Fate within Keratinocytes in Human Skin Pigmentation
Integrative and Comparative Biology, 2021
Synopsis Human skin and hair pigmentation play important roles in social behavior but also in photoprotection from the harmful effects of ultraviolet light. The main pigments in mammalian skin, the melanins, are synthesized within specialized organelles called melanosomes in melanocytes, which sit at the basal layer of the epidermis and the hair bulb. The melanins are then transferred from melanocytes to keratinocytes, where they accumulate perinuclearly in membrane-bound organelles as a “cap” above the nucleus. The mechanism of transfer, the nature of the pigmented organelles within keratinocytes, and the mechanism governing their intracellular positioning are all debated and poorly understood, but likely play an important role in the photoprotective properties of melanin in the skin. Here, we detail our current understanding of these processes and present a guideline for future experimentation in this area.
Medical & Biological Engineering & Computing, 1998
The melanin pigment system in human skin is extraordinarty welt developed and assures the photoprotection of the skin against harmful solar radiation. Specific cellcell interactions between one melanocytes and keratinocytes play a fundamental role in the regulation of melanogenesis and melanin pigementation, the two key elements of this system, giving rise to the concept of a structural, functional collaborative 'epidermal melanin unit,' Early experiments strongly suggested that melanocyte growth and differentiation are regulated by paracrine factors from keratinocytes and other skin cells. In addition, co-culture studies with keratinocytes has shown that the extracellular matrix acts as a local environmental signal for dendrite formation and melanogenesis. Attempts to reconstruct pigmented human skin in vitro have made great progress over the fast decade.
In vivo and in vitro evidence of dermal fibroblasts influence on human epidermal pigmentation
Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society, 2006
Using chimeric human epidermal reconstructs, we previously demonstrated that epidermal pigmentation is dependent upon the phototype of melanocytes. We report here several lines of experimental evidence for dermal modulation of human epidermal pigmentation. First, phototype II-III epidermal reconstructs grafted on the back of immunotolerant Swiss nu/nu mice developed a patchy pigmentation dependent on the presence of colonizing human or mouse fibroblasts. Similarly, human white Caucasoid split-thickness skin xenografted on the same mouse strain became black within 3 months and histochemistry revealed a phototype VI pattern of melanin distribution. In vitro, human fibroblasts colonizing human dead de-epidermized dermis (DDD) induced a decrease in epidermal pigmentation whereas mouse (Swiss nu/nu) fibroblasts increased epidermal pigmentation. Conditioned medium from mice (Swiss nu/nu) fibroblasts also increased pigmentation whereas conditioned medium from human fibroblasts had no signi...
Melanocyte Distribution and Function in Human Skin
From Melanocytes to Melanoma
Catalytic entities involved in melanin synthesis (including tyrosinase [TYR], tyrosinase-related protein 1 [TYRP1], and dopachrome tautomerase [DCT]) and structural proteins important to the integrity of melanosomes (including GP100/Pmel17) play active roles in the maintenance of the function and structure of those organelles produced by melanocytes. Constitutive skin pigmentation is regulated by a number of distinct factors (including melanocyte dendricity, transport of melanosomes to dendrites, and transfer of melanosomes to keratinocytes and their subsequent distribution) and can be affected by paracrine factors (from neighboring keratinocytes and fibroblasts) and the environment, including ultraviolet (UV) radiation, that regulate melanocyte proliferation and function. Because UV is inherently associated with photocarcinogenesis in the skin, including melanoma, we discuss melanocyte density and function, melanin content and distribution, DNA damage (measured by 6,4-phytoproducts [64PP] and cyclobutane pyrimidine dimers [CPD]) and apoptosis (measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling [TUNEL] staining) in response to UV in three different types of skin. In sum, UV-induced DNA damage in the lower epidermis is not effectively prevented in light/fair skin and UV-induced apoptosis is not seen in light skin after low doses of UV. These observations suggest that the combination of decreased DNA damage and more efficient removal of UV-damaged cells plays an important role in the decreased photocarcinogenesis seen in darker skin.
Cutaneous Photobiology. The Melanocyte vs. the Sun: Who Will Win the Final Round?
Pigment Cell Research, 2003
Solar ultraviolet radiation (UV) is a major environmental factor that dramatically alters the homeostasis of the skin as an organ by affecting the survival, proliferation and differentiation of various cutaneous cell types. The effects of UV on the skin include direct damage to DNA, apoptosis, growth arrest, and stimulation of melanogenesis. Long‐term effects of UV include photoaging and photocarcinogenesis. Epidermal melanocytes synthesize two main types of melanin: eumelanin and pheomelanin. Melanin, particularly eumelanin, represents the major photoprotective mechanism in the skin. Melanin limits the extent of UV penetration through the epidermal layers, and scavenges reactive oxygen radicals that may lead to oxidative DNA damage. The extent of UV‐induced DNA damage and the incidence of skin cancer are inversely correlated with total melanin content of the skin. Given the importance of the melanocyte in guarding against the adverse effects of UV and the fact that the melanocyte h...
Epidermal Keratinocytes from Light vs. Dark Skin Exhibit Differential Degradation of Melanosomes
Journal of Investigative Dermatology, 2011
Modification of skin complexion coloration has traditionally been accomplished by interruption or attenuation of melanogenesis and/or melanosome transfer. Post-transfer modification of pigmented melanosomes provides an attractive and distinct avenue of modulating skin pigmentation. The processing of melanosomes during keratinocyte (KC) terminal differentiation and the degradative variability observed between light and dark skin (LS and DS) remains enigmatic. To evaluate this, we developed a model system to investigate the loss of fluorescently labeled and isolated melanosomes by cultured human KCs. The extent of melanosome loss has been qualitatively assessed using transmission electron microscopy and indirect immunofluorescence with confocal microscopy, and quantitatively assessed using flow cytometry analysis. Results show that melanosomes are incorporated into the cytoplasm of both light and dark keratinocytes (LKCs and DKCs) and trafficked to a perinuclear region. Within 48 hours, confocal microscopy images suggest that LKCs display accelerated melanosome loss. This time-dependent decrease in carboxyfluorescein diacetate (CFDA) fluorescence was then quantitatively analyzed using flow cytometry. Consistent with the results of the confocal analysis, over a 48-hour time frame, LKCs appear to lose melanosomes more efficiently than DKCs. These experiments show that melanosomes are more rapidly lost in KCs derived from LS as opposed to DS. Abbreviations: CFDA, carboxyfluorescein diacetate; DKC, dark keratinocyte; DS, dark skin; KC, keratinocyte; LKC, light keratinocyte; LS, light skin; Md X, median X; PE, R-phycoerythrin; TEM, transmission electron microscopy Yoshida Y, Hachiya A, Sriwiriyanont P et al. (2007) Functional analysis of keratinocytes in skin color using a human skin substitute model composed of cells derived from different skin pigmentation types.
The FASEB Journal, 2007
Skin color is one of the most distinct features in the human race. To assess the mechanisms of skin color variation, human skin substitutes (HSS) were constructed by grafting mixtures of cultured keratinocytes and melanocytes from a combination of donor skin types, together with light skin derived fibroblasts, into chambers inserted onto the back skin of severe combined immunodeficient (SCID) mice. The resulting complexion coloration of the HSS was relatively darker and lighter when dark and light skin derived keratinocytes, respectively, were combined with melanocytes derived from either light or dark skin. The melanin content in the epidermis and the maturation stage of melanosomes in basal keratinocytes were significantly increased in the HSS composed of dark compared to light skin derived keratinocytes. In addition, the ratio of individual/clustered melanosomes in recipient keratinocytes was increased in the former as opposed to the latter HSS. The genetic expression of endothelin-1, proopiomelanocortin, microphthalmiaassociated transcription factor, tyrosinase, GP100, and MART1 were increased in HSS composed of dark vs. light skin derived keratinocytes. These data suggest that our HSS is a promising melanogenic model that demonstrates the role of the keratinocyte in regulating in part both melanogenesis and distribution of transferred melanosomes.-Yoshida, Y., Hachiya, A., Sriwiriyanont, P., Ohuchi, A., Kitahara, T., , Y., Visscher, M. O., Boissy, R. E. Functional analysis of keratinocytes in skin color using a human skin substitute model composed of cells derived from different skin pigmentation types. FASEB J. 21, 2829 -2839 (2007)
Shedding Light on Melanocyte Pathobiology In Vivo
Cancer Research, 2012
Cutaneous malignant melanoma is rapidly increasing in the developed world and continues to be a challenge in the clinic. Although extensive epidemiological evidence points to solar ultraviolet radiation (UV) as the major risk factor for melanoma, there is a significant gap in our knowledge about how this most ubiquitous environmental carcinogen interacts with the largest organ of the mammalian body (skin) at the microenvironmental and molecular level. We review some recent advances that have started to close this gap.