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      Race Does Not Predict Melanocyte Heterogeneous Responses to Dermal Fibroblast-Derived Mediators

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          Abstract

          Introduction

          Abnormal pigmentation following cutaneous injury causes significant patient distress and represents a barrier to recovery. Wound depth and patient characteristics influence scar pigmentation. However, we know little about the pathophysiology leading to hyperpigmentation in healed shallow wounds and hypopigmentation in deep dermal wound scars. We sought to determine whether dermal fibroblast signaling influences melanocyte responses.

          Methods and Materials

          Epidermal melanocytes from three Caucasians and three African-Americans were genotyped for single nucleotide polymorphisms (SNPs) across the entire genome. Melanocyte genetic profiles were determined using principal component analysis. We assessed melanocyte phenotype and gene expression in response to dermal fibroblast-conditioned medium and determined potential mesenchymal mediators by proteome profiling the fibroblast-conditioned medium.

          Results

          Six melanocyte samples demonstrated significant variability in phenotype and gene expression at baseline and in response to fibroblast-conditioned medium. Genetic profiling for SNPs in receptors for 13 identified soluble fibroblast-secreted mediators demonstrated considerable heterogeneity, potentially explaining the variable melanocyte responses to fibroblast-conditioned medium.

          Discussion

          Our data suggest that melanocytes respond to dermal fibroblast-derived mediators independent of keratinocytes and raise the possibility that mesenchymal-epidermal interactions influence skin pigmentation during cutaneous scarring.

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          Most cited references 37

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          Human pigmentation genes: identification, structure and consequences of polymorphic variation.

          The synthesis of the visible pigment melanin by the melanocyte cell is the basis of the human pigmentary system, those genes directing the formation, transport and distribution of the specialised melanosome organelle in which melanin accumulates can legitimately be called pigmentation genes. The genes involved in this process have been identified through comparative genomic studies of mouse coat colour mutations and by the molecular characterisation of human hypopigmentary genetic diseases such as OCA1 and OCA2. The melanocyte responds to the peptide hormones alpha-MSH or ACTH through the MC1R G-protein coupled receptor to stimulate melanin production through induced maturation or switching of melanin type. The pheomelanosome, containing the key enzyme of the pathway tyrosinase, produces light red/yellowish melanin, whereas the eumelanosome produces darker melanins via induction of additional TYRP1, TYRP2, SILV enzymes, and the P-protein. Intramelanosomal pH governed by the P-protein may act as a critical determinant of tyrosinase enzyme activity to control the initial step in melanin synthesis or TYRP complex formation to facilitate melanogenesis and melanosomal maturation. The search for genetic variation in these candidate human pigmentation genes in various human populations has revealed high levels of polymorphism in the MC1R locus, with over 30 variant alleles so far identified. Functional correlation of MC1R alleles with skin and hair colour provides evidence that this receptor molecule is a principle component underlying normal human pigment variation.
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            Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion.

            Recent studies have described the role of shedding vesicles as physiological conveyers of intracellular components between neighboring cells. Here we report that melanosomes are one example of shedding vesicle cargo, but are processed by a previously unreported mechanism. Pigment globules were observed to be connected to the filopodia of melanocyte dendrites, which have previously been shown to be conduits for melanosomes. Pigment globules containing multiple melanosomes were released from various areas of the dendrites of normal human melanocytes derived from darkly pigmented skin. The globules were then captured by the microvilli of normal human keratinocytes, also derived from darkly pigmented skin, which incorporated them in a protease-activated receptor-2 (PAR-2)-dependent manner. After the pigment globules were ingested by the keratinocytes, the membrane that surrounded each melanosome cluster was gradually degraded, and the individual melanosomes then spread into the cytosol and were distributed primarily in the perinuclear area of each keratinocyte. These results suggest a melanosome transfer pathway wherein melanosomes are transferred from melanocytes to keratinocytes via the shedding vesicle system. This packaging system generates pigment globules containing multiple melanosomes in a unique manner.
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              Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling.

              During wound healing, stem cells provide functional mature cells to meet acute demands for tissue regeneration. Simultaneously, the tissue must maintain a pool of stem cells to sustain its future regeneration capability. However, how these requirements are balanced in response to injury is unknown. Here we demonstrate that after wounding or ultraviolet type B irradiation, melanocyte stem cells (McSCs) in the hair follicle exit the stem cell niche before their initial cell division, potentially depleting the pool of these cells. We also found that McSCs migrate to the epidermis in a melanocortin 1 receptor (Mc1r)-dependent manner and differentiate into functional epidermal melanocytes, providing a pigmented protective barrier against ultraviolet irradiation over the damaged skin. These findings provide an example in which stem cell differentiation due to injury takes precedence over stem cell maintenance and show the potential for developing therapies for skin pigmentation disorders by manipulating McSCs.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                29 September 2015
                2015
                : 10
                : 9
                Affiliations
                University of Washington Department of Surgery, Seattle, Washington, United States of America
                Rutgers University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PS NSG AMH. Performed the experiments: PS JSA LAM CTL LQ MS. Analyzed the data: PS RFS MS LAM LQ NSG. Contributed reagents/materials/analysis tools: RFS. Wrote the paper: PS LAM AMH RFS NSG.

                [¤a]

                Current address: Division of Plastic Surgery, Department of Surgery, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand

                [¤b]

                Current address: Department of Plastic and Reconstructive Surgery National Yang-Ming University School of Medicine; Kaohsiung City, Taiwan

                [¤c]

                Current address: Department of Burn and Plastic Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

                Article
                PONE-D-15-21064
                10.1371/journal.pone.0139135
                4587942
                26418010

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 6, Tables: 2, Pages: 15
                Product
                Funding
                Support was provided by National Institutes of Health grants (R01GM089704; T32 GM007037).
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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