Melanocyte Stem Cells In Hair Follicles Research Articles

Micro-Injury Induces Hair Regeneration and Vitiligo Repigmentation Through Wnt/β-Catenin Pathway.

Extrinsic injury can evoke intrinsic stimulation and subsequently initiate the physiological repair process. This study aims to investigate whether clinically acceptable micro-injury could be used to create local stimuli to induce hair regeneration and vitiligo repigmentation. A novel device was designed and manufactured to precisely control the micro-injury parameters. Then the most appropriate extent of micro-injury without over-damaging the skin was evaluated. Finally, the effects of micro-injury on hair regeneration and vitiligo repigmentation were examined by macroscopic observation, histological staining, gene and protein expression analysis. We discover that proper micro-injury effectively induces hair regeneration by activating the hair follicle stem cell proliferation and migration downwards to the hair matrix, finally shifting the hair follicle stage from telogen into anagen. On vitiligo model mice, micro-injury also induces the hair follicle melanocyte stem cells to migrate upwards to the interfollicular epidermis, activating and giving rise to melanocytes to repopulate the vitiligo lesion. Mechanistic analysis indicates that the canonical Wnt/β-catenin pathway plays a key role in the micro-injury-induced repair process. This study demonstrates that micro-injury has great potential in inducing hair regeneration and vitiligo repigmentation, laid a foundation to develop a micro-injury-based treatment method in alopecia and vitiligo.

SCF/c-kit signaling is required in 12-O-tetradecanoylphorbol-13-acetate-induced migration and differentiation of hair follicle melanocytes for epidermal pigmentation.

Hair follicle melanocyte stem cells (McSCs) are responsible for hair pigmentation and also function as a major melanocyte reservoir for epidermal pigmentation. However, the molecular mechanism promoting McSCs for epidermal pigmentation remains elusive. 12-O-tetradecanoylphorbol-13-acetate (TPA) mimics key signaling involved in melanocyte growth, migration and differentiation. We therefore investigated the molecular basis for the contribution of hair follicle McSCs to epidermal pigmentation using the TPA induction model. We found that repetitive TPA treatment of female C57BL/6 mouse dorsal skin induced epidermal pigmentation by increasing the number of epidermal melanocytes. Particularly, TPA treatment induced McSCs to initiate proliferation, exit the stem cell niche and differentiate. We also demonstrated that TPA promotes melanoblast migration and differentiation in vitro. At the molecular level, TPA treatment induced robust expression of stem cell factor (SCF) in keratinocytes and c-kit in melanoblasts and melanocytes. Administration of ACK2, a neutralizing antibody against the Kit receptor, suppressed mouse epidermal pigmentation, decreased the number of epidermal melanocytes, and inhibited melanoblast migration. Taken together, our data demonstrate that TPA promotes the expansion, migration and differentiation of hair follicle McSCs for mouse epidermal pigmentation. SCF/c-kit signaling was required for TPA-induced migration and differentiation of hair follicle melanocytes. Our findings may provide an excellent model to investigate the signaling mechanisms regulating epidermal pigmentation from mouse hair follicle McSCs, and a potential therapeutic option for skin pigmentation disorders.

Finding a niche

One of the wonders of development is the long migration undertaken by cells of the neural crest to their final destinations where they undergo differentiation. For cells of the melanocyte lineage, migration is driven by the ability of melanoblasts to receive and interpret extracellular cues that control their rate of proliferation and give directional signals so that they take the correct route. This intrinsic capacity of neural crest cells for long-distance movement may be one reason why melanomas are so aggressive; oncogene-mediated deregulation of key developmental signal transduction pathways coupled with microenvironmental stress may be sufficient to reactivate the embryonic migratory potential without the need for acquisition of pro-metastasis mutations. The processes underpinning development and those implicated in melanoma genesis and progression are intimately related, and the lessons from one system are likely to be applicable to the other. One key concern is the origin of melanoma: do the initial mutational events that lead to malignant transformation occur in differentiated melanocytes or their stem cells? Given that differentiated cells most likely have heterochromatinized the genes required for proliferation, the melanocyte stem cell might represent an attractive candidate. Moreover, there is increasing evidence that the heterogeneity observed within a melanoma may in part reflect the presence of ‘melanoma stem cells’ that would provide a reservoir of potentially drug-resistant cells with a capacity to form new tumours. Understanding how such a population of melanoma stem cells might be generated, and how the microenvironment might control the switch from proliferation to quiescence and vice versa is a key issue in the field. Presumably the tumour microenvironment will provide a ‘niche’ that is permissive for the generation and maintenance of the melanoma stem cell population. However, the dynamic nature of melanoma provides major challenges to understanding the nature of the putative melanoma stem cell niche. By contrast, understanding the molecular mechanisms that lead to the generation, maintenance and re-activation of normal melanocyte stem cells is tractable. Advances made over recent years, particularly by the Nishikawa laboratory, first identified melanocyte stem cells in the hair follicle bulge region and subsequently led to the molecular characterization of the hair follicle melanocyte stem cells in terms of their gene expression characteristics. The results obtained provide the basis for addressing a key question in stem cell biology: what determines a stem cell niche? The review from Masatake Osawa and Shin-Ichi Nishikawa in this issue summarizes the progress made to date on the characterization of melanocyte stem cells and proposes a model to describe the events that lead to the generation of a melanocyte stem cell. Although there is yet a long way to go, it is clear that unlike most other stem cell systems, the melanocyte lineage provides an excellent model for defining what is required for a stem cell niche. Importantly, the answers obtained to date suggest that melanocyte and melanoma stem cells may have a great deal in common. While melanoma represents a potentially fatal disease of the melanocyte lineage, it is relatively well characterized at the molecular level compared with vitiligo, a disease in which there is loss of melanocytes in the skin. While not life threatening, vitiligo nevertheless represents a major challenge to our understanding of pigment cell biology and as pointed out by Alain Taieb in his News and Views article, there is no obvious angle of attack. Although there is evidence that one component of the disease is stress sensitivity, one aspect that is undoubted is that vitiligo is characterized by a cell-based immune response against differentiated melanocytes and that this is underpinned by a genetic component. The current status of the genetics of vitiligo is reviewed by Rich Spritz, who not only highlights specific candidate genes for the disease, but also points out several candidates that appear to have fallen by the wayside. Progress in understanding vitiligo is likely to require a very broad approach in multiple disciplines, but rigorous application of statistics to genetic analysis will be critical if any progress in identifying true vitiligo-associated genes is to be made. Moreover, while understanding the molecular basis of vitiligo is clearly important, there is an urgent need for more effective treatment now. In that respect, while the immune response may eliminate differentiated melanocytes, the melanocyte stem cells in their niche do not express melanocyte markers and therefore will escape destruction. Understanding the mechanisms that lead to reactivation of the stem cell population and consequent repopulation of de-pigmented skin with new melanocytes represents the most viable approach for an effective anti-vitiligo therapy. Again, the review from Osawa and Nishikawa in this issue provides a sound basis for studies directed towards stem cell-based vitiligo therapy.

Highlights in DD

“Highlights” is a feature that calls attention to exciting advances in developmental biology that have recently been reported in Developmental Dynamics. Development is a broad field encompassing many important areas. To reflect this fact, the section will spotlight significant discoveries that occur across the entire spectrum of developmental events and problems: from new experimental approaches, to novel interpretations of results, to noteworthy findings utilizing different developmental organisms. Do the Strand (Dev Dyn 2007;236:84–92) In this Special Focus Research Article on the enteric nervous system (ENS), Druckenbrod and Epstein describe behaviors of migratory enteric neural crest-derived cells (ENCCs) as they populate the ENS. ENCCs follow a wavefront where connected chains of cells, or strands, form and extend to the gut mesenchyme. Using time-lapse imaging in chick and mice, the authors document how three cell types, distal, rostral, and anterior cells (DCs, RCs, ACs), influence overall strand dynamics. DCs, the leading cells of strands, are exploratory, extending filopodia and changing trajectories during their rostral to caudal route. RC dynamics vary with respect to distance from the wavefront; they chiefly elongate and maintain the integrity of strands. ACs play a prominent role in colonization of the cecum and proximal colon. Like RCs, they elongate strands, and also influence DC trajectories. Potential mechanisms that guide the intricate strand cell dance are discussed. Time Is of the Essence (Dev Dyn 2007;236:142–155) Most are familiar with the concept that circadian rhythms dictate when you are prone to feeling sleepy or wakeful. But did you know that the cell cycle in proliferating bone marrow is also synchronized to day–night cycles? These facts and much more are brought to light in this compelling review on circadian rhythm. The article not only covers the molecular bases and physiological outputs of circadian rhythm, but also development of circadian timing and the impact of development on the circadian clock. Is early embryonic development also under the spell of day–night rhythms? Read the review to find out. Going Gray (Dev Dyn 2007;236:282–289) It is tempting to blame newfound gray hairs on mounting stresses at work. This paper highlights another possible cause, malfunctioning Notch receptors. During hair growth, melanocytes deliver pigment to the hair matrix. As the melanocyte stem cell population is depleted, hair pigmentation decreases, producing gray hair. The authors show that mice with a conditional deletion of Notch 1 or 2 from melanocytes undergo premature graying; eye pigmentation is unaffected. Moreover, graying is dose-dependent; it is accelerated upon deletion of additional Notch1/2 alleles. The underlying defect is precocious depletion of Dct-expressing cells, which labels melanoblasts and melanocytes. This work suggests that Notch 1 and 2 have overlapping functions in regulating self-renewal of hair follicle melanocyte stem cells.