Relevance of genes involved in skin tissue formation to human diseases and its application for regenerative medicine.

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This research project is aiming to identify genes involved in the formation of skin and to develop therapeutic measures based on the molecular mechanisms of the gene products. Major results obtained are as follows.1.Growth regulation of human keratinocytes : A novel pathway involving S100C/A11We found that a Ca-binding protein S100C/A11 mediates the growth inhibitory signal of both high Ca and TGFβ which are representative growth suppressors for normal human keratinocytes. On exposure to high Ca or TGFβ, S100C/A11 was phosphorylated by PKCα and transferred to nuclei, where it induced p21/WAF1 through activation of Sp1. In addition to this common pathway, we showed that the well-known unique pathways, the NFAT1-mediated and Smad-mediated pathways for high Ca and TGFβ, respectively, were indispensable for the growth inhibition.2.Keratinization of epidermal keratinocytes : Characterization of newly-isolated gene, hornerinHornerin is a newly isolated gene, which has common structural features with profilaggrin, a key protein for keratinization. In adult mouse, hornerin was expressed in stratified epithelial cells of the skin, tongue, esophagus, and forestomach. We also isolated and characterized the human ortholog. Unexpectedly, hornerin protein was not detected in normal adult trunk skin but induced in the regenerating epidermis and psoriatic epidermis.3.Differentiation of adult bone marrow cells into skin cellsWe established a skin reconstitution system by inoculating a suspension of mouse embryonic skin cells into a silicon chamber on the back of nude mice. We showed that adult mouse bone marrow cells were differentiated into skin cells including cells forming epidermis, hair follicles, and sebaceous glands when transplanted with the embryonic skin cells.4.Isolation of stem cells from mouse embryonic skinWe isolated stem cells by inoculating mouse embryonic skin cells into a thermo-sensitive synthetic gel.