Regulating melanosome transfer: who’s driving the bus?

Pigmentation of the skin has important consequences with respect to survival, not the least of which in humans is photoprotection from ultraviolet (UV) radiation. Thus in addition to serving as the major determinant dividing us into various racial and ethnic groups, skin pigmentation protects us from photocarcinogenesis and according to statistics of the National Cancer Institute for 2006, those in the United States with less pigmented skin are ∼70 times more likely to develop squamous or basal cell carcinomas and ∼20 times more likely to develop melanomas as are those with darkly pigmented skin. Skin pigmentation depends not only on the production of melanin by melanocytes but importantly depends on the transfer of that melanin to adjacent keratinocytes and its distribution towards the surface of the skin. Functional melanocytes are essential to this process of course, but keratinocytes also play a crucial role in determining skin color. A recent study (Yoshida et al., 2007) provides important new insights into the role of keratinocytes in determining visible color in different skin phenotypes. More than 120 distinct genes regulate mammalian pigmentation (Bennett and Lamoreux, 2003), working at various levels to determine the development and distribution of melanocytes, their differentiation and their regulation by physiological factors. Great strides have been made in understanding those processes and how they interact to regulate visible pigmentation. Yet none of the pigment genes identified have been associated with defects in melanosome transfer from melanocytes to keratinocytes. One human disease has been associated with defects in melanosome transfer, guttate leucoderma (Jimbow, 1997), and several factors have been identified recently that play roles in the transfer (protease-activated receptor 2 (PAR2) and keratinocyte growth factor (KGF)). Many studies over the years have shown that melanocytes in mono-culture are competent to secrete melanosomes to the extracellular milieu and that this process can be regulated physiologically, e.g. by UV radiation and by alpha-melanocyte stimulating hormone (αMSH). Keratinocytes in mono-culture are competent and efficient in phagocytosing melanosomes from the medium, and again, that process can be regulated physiologically. However, despite many attempts to observe the actual transfer of melanosomes between those two types of cells, either in skin or in artificial skin models, there is no consensus on how that process occurs or is modulated in melanocytes or in keratinocytes (Boissy, 2003; Seiberg, 2001; Van Den Bossche et al., 2006). The biosynthesis of melanin, the biogenesis of melanosomes and the movement of melanosomes to the dendrites of melanocytes are all pretty well characterized at this point, yet the transfer process from melanocytes to keratinocytes remains a ‘black box’. Progress on unraveling the mechanism of melanosome transfer is being made in small increments. Earlier studies revealed that melanosome transfer and subsequent distribution of melanosomes in keratinocytes was regulated and differed in skin of various racial/ethnic groups (Gibbs et al., 2000; Minwalla et al., 2001; Okazaki et al., 1976; Yamamoto and Bhawan, 1994). Later studies showed that the process could be mimicked in co-culture models and could be regulated by physiological agents (Virador et al., 2002), but still no light was shed on the actual process involved. Other groups have reported the involvement of ligands (such as KGF) and receptors (such as PAR2) in regulating uptake of melanosomes by keratinocytes (Cardinalli et al., 2005; Greatens et al., 2005; Scott et al., 2001; Seiberg, 2001). Earlier studies by the Boissy group demonstrated that keratinocytes played an integral role in the transfer of melanosomes and determined the way the ingested melanosomes were subsequently distributed (Boissy, 2003; Boissy and Nordlund, 1997; Thong et al., 2003). However, the relatively slow nature of the transfer process, and the limited times for observation of effects in co-culture and in artificial skin models has heretofore hindered investigations of the mechanism(s) involved in melanosome transfer between melanocytes and keratinocytes. Yoshida et al. took the novel approach of establishing a long-term model in which to observe the involvement of different types of cells, and regulators of melanosome transfer, on eventual skin color. They devised a model in which they could supply various combinations of epidermal cells (i.e. melanocytes and keratinocytes) derived from skin of different racial-ethnic origins, and grow them in skin grafts on SCID mice. They could combine cells derived from light-skinned donors and/or dark-skinned donors, place them into grafts on the dorsal skin of SCID mice, and then observe the effects for weeks or months thereafter. Using that model, they found that keratinocytes play a significant role in determining the amount and type of melanin produced by melanocytes, the number of melanosomes that are transferred from melanocytes and their eventual distribution patterns in keratinocytes (i.e. individually or in clusters). This not only proves that keratinocytes are integrally involved in melanosome transfer and are not just inactive bystanders, but also they play a significant role in regulating melanocyte differentiation, in itself an exciting finding. Keratinocytes derived from dark-skinned donors markedly stimulated the expression of melanogenic proteins (e.g. MITF, tyrosinase, Pmel17 and MART1) of melanocytes, regardless of whether the melanocytes were derived from light- or dark-skinned donors. This new model system not only provides important insights into the significant roles of keratinocytes in determining skin color, but provides an important model that should allow further characterization of the system, not only to determine the physiological processes involved in the transfer process per se, but also into the signaling mechanisms by which the keratinocytes help determine melanocyte function.