Current topics in skin pigmentation
- 開催年月 ：
- 共催 ：
1）Chairperson:Masako Mizoguchi, M.D., Ph.D.
St. Marianna University School of Medicine
Masatake Osawa, Ph.D.
Cutaneous Biology Research Center
Center for Regenerative Medicine
Massachusetts General Hospital/Harvard Medical School
Shiseido Research Center
Melanocyte stem cells: as a model to study stem cell biology
Masatake Osawa, Ph. D.（Assistant Professor Cutaneous Biology Research Center Center for Regenerative Medicine Massachusetts General Hospital/Harvard Medical School ）
Elucidation of molecular mechanisms underlying stem cell regulation is of great importance both for developmental biology and for clinical applications in regenerative medicine and cancer therapy. However, because of difficulties in identifying and manipulating stem cells and their surrounding components in situ, the exact mechanisms underlying the stem cell regulation remain elusive. In mice, melanocyte stem cells (MSCs) are specifically localized at the bulge area of the hair follicle where individual MSCs are anatomically segregated from their differentiated progenies in the hair matrix. Given the capability of locating individual MSCs, MSCs offer an advantageous model to clarify how stem cells are regulated by their surrounding microenvironment. Furthermore, as it has been demonstrated that loss-of-functional mutations in the genes responsible for MSC maintenance result in premature hair graying, MSCs provide an excellent phenotype-base screening system in which genes required for stem cell regulation are allowed to be isolated based on the hair graying phenotype. To clarify molecular mechanisms underlying MSC regulation, we compared transcriptional profiles of various subsets of immature melanoblast populations, and obtained a cluster of genes that is transiently upregulated in melanoblasts at the onset when they get in a dormant status at the bulge region. These genes include molecules encoding transcription factors, adhesion proteins and stress responsible molecules, suggesting that a complex of signals is implicated in MSC regulation. By integrating the gene expression profile and lentivirus-mediated gene knockdown transgenesis technology, we are currently generating melanoyte-specific knockdown transgenic mice to isolate genes involved in MSC regulation. Thus, by employing MSCs as model system to study stem cell biology, we hope to provide new insights into our understanding of the nature of stem cell regulation at the molecular level.
A mechanism of hyperpigmentation - immunohistochemical and transcriptional analysis of pigmented lesions
Hirofumi Aoki（Research Scientist Shiseido Research Center ）
Solar lentigo appears as dark brown spots that occur on sun-exposed areas and considered to be a hallmark of aged skin. To clarify further the mechanisms underlying the development of solar lentigo, we examined gene expression profile in skin biopsy specimens obtained from the back of human solar lentigines using DNA microarray analysis. In comparison with sun-protected skin, many inflammation-related genes in addition to melanocyte related genes were up-regulated in solar lentigo, whereas in comparison with sun-exposed control skin, up-regulation of genes related to fatty acid metabolism was apparent. Moreover, we found down-regulation of cornified envelope-related genes, which suggests suppression of cornification in the epidermis in solar lentigo. Immunohistochemically, TRP-1-positive cells increased two fold and expression of filaggrin and involucrin was decreased in the lesional skin, where the number of cell layers of the stratum corneum was significantly higher than in normal skin. On the other hand, there were less dividing keratinocytes in solar lentigo and most of them contained few melanin. The rate of division of melanin containing keratinocytes is one-sixth of those without melanin in solar lentigo. We added melanin to normal human keratinocytes cell culture in order to simulate basal keratinocytes of solar lentigo. As a result, we found that the number of dividing cells was decreased in a dose-dependent manner to melanin amount added in the culture after phagocytosis.
The results of the present analysis of solar lentigo, demonstrating up-regulation of genes related to inflammation, fatty acid metabolism and melanocytes and down-regulation of cornified envelope-related genes, suggest that solar lentigo is induced by the mutagenic effect of repeated ultraviolet light exposures in the past, together with decreased division of melanin containing keratinocytes, which result in the chronic pigment accumulation in lesional keratinocytes.