Many are called, few are chosen

The ability to regenerate tissues is dependent on a reservoir of stem cells, that given appropriate cues, divide to yield both a transit amplifying progeny that go on to differentiate, as well as cells that will replenish the stem cell population. The understanding of stem cell biology, the signals that induce their quiescence and activation, and the environment that constitutes their niche are crucial to the future of regenerative medicine, and have major implications for cancer therapy. Melanocytes, their origin from the neural crest, and their physiological and malignant stem cells represent a powerful model system for stem cell biology in general. To reflect that, this issue brings together several articles in which these key features of the melanocyte lineage are discussed. The neural crest gives rise to the vast majority of pigment cells, with the notable exception of the retinal pigment epithelium. The thoughtful Perspective from Lukas Sommer turns the spotlight onto the microenvironmental signals and transcription regulators that drive multipotent neural crest cells towards a melanocyte fate. One conclusion is that while several key genes have been identified that play crucial roles in the identity, proliferation, migration and differentiation of melanoblasts, additional factors other than FoxD3, Pax3, Mitf and Sox10 must participate in the program that specifies a cell of the melanocyte lineage and represses alternative fates. The identification of such factors will be a key focus for future work and will have implications, not only for the generation of the melanocyte lineage, but also for melanoma whose invasive and proliferative properties are related to the migratory and proliferative capacity of neural crest-derived melanoblasts. Many thousands of melanoblasts exit the neural crest during development to populate the hair follicles, epidermis and other sites with differentiated melanocytes. Only a few, however, adopt an alternative fate to become melanocyte stem cells characterized by dormancy and absence of differentiation markers. Two Perspectives from Emi Nishimura, and Zabierowski et al., highlight the characteristics of melanocyte stem cells found in the hair follicle niche and the dermis respectively. Unlike differentiated pigment cells, melanocyte stem cells were first identified in the bulge region of the hair follicle in 2002 by Emi Nishimura while in Shin-ichi Nishikawa’s lab. Since then several key insights have been gained. For example, hair graying is a result of a failure of the melanocyte stem cell function, DNA damage can induce differentiation of melanocyte and other stem cells, and the role of and source of TGFb in establishing the stem cell population has been characterized. Nevertheless many key questions remain to be addressed, including what induces only a very minor subset of melanoblasts to enter the niche and adopt a quiescent stem cell fate, and do the stem cells exhibit a specific program of gene expression, given that they appear to be largely transcriptionally quiescent? While a great deal of work has been focused on the hair follicle associated stem cells, less attention has been given to dermal melanocyte stem cells. The current state-of-theart regarding these cells, much of the work originating from Meenhard Herlyn’s lab, is covered in the timely Perspective from Zabierowski et al. The existence of non-follicular stem cells had been long hypothesized and this review covers their characteristics in terms of localization, markers and biological properties, especially in terms of their ability to generate multiple cell types. Significantly, it is possible that long-lived dermal stem cells may be a cell of origin for melanoma, especially for those melanomas that originate from areas of the body that are devoid of hair. The relationship between melanocyte stem cells from the hair follicle or the dermis and putative melanoma stem cells has received a great deal of attention over recent years. Melanoma stem cells have been proposed to be responsible for tumour initiation and therapeutic resistance, as well as the generation of the heterogenous cell populations found in tumours. A rapidly expanding literature covers a variety of markers that have been proposed to distinguish this key population from others, including ABCB5 and CD271 ⁄ NGFR in melanoma in vivo, and expression of JARID1B or absence of Mitf in cultured melanoma cells. However, while it is generally accepted that melanomas do contain stem-like cells, generated most likely by a process termed phenotypeswitching, there is a great deal of controversy about the usefulness of the different markers identified to date in the identification of bona fide melanoma stem cells. In this issue, Landreville et al. report another melanoma marker, ABCB1, that marks a highly metastatic subpopulation of uveal melanoma cells that may exhibit many of the properties associated with stem like cells. The identification of this marker may open up better therapeutic strategies for dealing with this highly aggressive melanoma subclass. Finally, the range of topics covered in this stem cell themed issue highlights the new insights and rapid progress made over recent years in characterizing the stem cells and origins of the melanocyte lineage. The results generated to date and in the future will make a major contribution to our understanding of stem biology in general, and lend weight to the argument that the melanocyte ⁄ melanoma system is one of the best models for addressing the outstanding questions in stem cell biology.