Elucidation of the mechanism of scarless wound healing and identification of its master gene

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Previous our studies have demonstrated that hyaluronan is one of important factors for scarless wound healing mechanism. In order to investigate its more details, we first analyzed gene expression in the fetal mouse skin, which scarless wound healing is observed, by serial analysis gene expression (SAGE) techniques. SAGE analyses revealed that over forty kinds of specific genes were detected. The genes for hyaluronan synthase (HAS), type VII collagen, and fibromodulin were upregulated, whereas HOX and PRX families, and TGF-beta genes were down regulated in dermal fibroblasts of scarless wound healing mice. Furthermore, addition of hyaluronan in dermal fibroblasts of adult mice, in which scarless wound healing,are not observed, resulted in similar expression pattern of scarless wound healing specific genes. These resulted suggested that treatment with hyaluronan may induce scarless wound healing mechanism in adult dermal fibroblasts. However, introductions the expression of each gene or its recombinant protein into the wounds of adult mice skin did not disappear scar formation. Therefore, each gene identified in these studies was not master gene of scarless wound healing. On the other hands, treatment of dermal fibroblasts of adult mice with 4-methylumbelliferon (MU), a hyaluronan synthase suppressor, resulted in opposite expression pattern of scarless wound healing specific genes. Oral administration of MU in adult mice caused severe scar formation. Furthermore, dryness and fragility of the skin were also observed, suggesting these mice are useful tools for investigating not only the molecular mechanism of scarless wound healing but also skin aging.