MELANOCYTE HETEROGENEITY
Human melanocytes reside not only in the epidermis and in hair follicles but also in mucosa, cochlea of the ear, iris of the eye, and mesencephalon of the brain as well as other tissues (Plonka et al. 2009). As far as mouse melanocytes are concerned, Aoki et al. reported that noncutaneous (ear, eye, and harderian gland) and dermal melanocytes are different from epidermal melanocytes in that the former do not respond to KIT stimulation but respond well to ET3 (endothelin 3) or HGF (hepatocyte growth factor) signals (Aoki et al. 2009), suggesting the heterogeneity of mouse melanocytes. They also reported that noncutaneous or dermal melanocytes cannot participate in regenerating follicular melanocytes using the hair reconstitution assay, unlike epidermal melanocytes (Aoki et al. 2011). Studies by Tobin’s group also support the hypothesis that follicular and epidermal melanocytes in human skin are different regarding their responses to various biological response modifiers, including αMSH (Tobin 2011). Additionally, Li et al. (2010) also reported that dermal melanocyte stem cells derived from glabrous human foreskin (i.e., with no hair follicles) can differentiate into functional epidermal melanocytes using a three-dimensional skin equivalent model.
These results make us wonder whether human fetal and/or adult melanocytes are heterogeneous. Human adult melanocytes in skin on the palms and soles may be different from melanocytes derived from other sites of the skin based on the facts that melanocyte migration stops at the palms and soles during embryogenesis and that skin on the palms and soles is hypopigmented and contains a fivefold lower density of melanocytes than at other skin areas. Additionally, fibroblasts in the dermis of the palms and soles secrete high levels of DKK1 (dickkopf1), which is an inhibitor of the Wnt signaling pathway and suppresses the proliferation and differentiation of those melanocytes (Yamaguchi et al. 2004). Preliminary results obtained from human fetal melanocytes cultured from four different body sites (scalp, back, abdomen, and sole) indicate that palmoplantar melanocytes express high levels of DKK1, TBX4, WIF1, FGF7, and CHI3L1 (Nakamura et al. 2012). Although the relevance to melanocytes has not been elucidated, a series of studies from Chang’s group showed that the expression patterns of homeotic genes (HOX genes, which are expressed in a nested pattern along developmental axes) determine positional identities within the human body (Chang 2009) and that a long noncoding RNA, which used to be considered to have nonspecific roles, has site-specificity (Rinn et al. 2007) and maintains active chromatin to coordinate HOX gene expression (Wang et al. 2011). Additionally, the expression levels of distal-specific HOXA13 are up-regulated in adult fibroblasts in the skin of paws of mice, thereby inducing the expression of Wnt5A, a morphogen required for distal development, in fibroblasts and of keratin 9, a distal specific marker of epidermis, in keratinocytes (Rinn et al. 2008). These results obtained in studies of mice support the hypothesis that mesenchymal-epithelial interactions play important roles in maintaining the site-specificity of the skin (Yamaguchi et al. 2005).
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Taken together, human fetal and adult melanocytes may be heterogeneous/site-specific because those melanocytes are also regulated and maintained by site-specific HOX genes, whose expression patterns are eventually determined by chromatins and long noncoding RNAs. That melanocyte heterogeneity may be affected both by intrinsic factors, including a site-specific transcription factor, HOX, and by extrinsic factors secreted by surrounding resident cell types: fibroblasts and keratinocytes. The fact that acral melanoma is different from other types of melanoma (Curtin et al. 2005), especially in that AMP kinase-related NUAK2 expression levels are high in patients with poor prognosis acral melanoma (Namiki et al. 2011), may also support the idea that melanocytes are heterogeneous.
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