Cultured epidermal sheets are reconstituted using keratinocytes only and easily produced in large-scale. Graft taking rate of cultured epidermal sheets is relatively low because of lack of cornified layer as well as basement membrane components. On the other hand living skin equivalent model (LSE) has dermal portion and cornified layer, and its taking rate are improved than cultured epidermal sheets. It is clearly demonstrated that LSE has basement membrane components that are not fully developed. We improved LSE using amnion membrane, and developed easy and fast production method for LSE. Furthermore clinical application is presented in this paper.Skin Research, Suppl. 17: 1-6, 2012

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Skin wound healing is mediated by inflammatory cell infiltration and subsequent cytokine production. Inducible co-stimulator (ICOS), expressed on activated T cells, and its ligand, ICOS ligand (ICOSL), expressed on antigen-presenting cells. To clarify the roles of ICOS-ICOSL pathway in skin wound healing, repair of excisional wounds was examined in ICOS^－/－ mice, ICOSL^－/－ mice, and ICOS^－/－ICOSL^－/－ mice. Each mutant strain showed dramatic delays in wound healing. Mutant mice showed diminished inflammatory cell infiltration. The loss of ICOS and/or ICOSL resulted in marked suppression of cytokine expression in wounds, especially interleukin (IL)-4, IL-6, and IL-10. T cell depletion therapy and T cell transfer experiments further clarified the important roles of ICOS expressed on T cells. The mRNA levels of Th2 cytokines were significantly lower in mutant mice. Application of IL-6 to the wounds significantly improved early wound healing in mutant mice. Our results indicate that ICOS-ICOSL signaling has crucial roles during wound healing, most likely by inducing IL-6 production.Skin Research, Suppl. 17: 7-13, 2012

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We summarized previous reports pertaining to effects of basic fibroblast growth factor (bFGF) on keratinocyte. It has been reported that bFGF promotes the healing of skin ulceration by inducing fibroblast proliferation. Interestingly, recent studies have demonstrated that bFGF induces human keratinocyte proliferation as well. Thus, we have hypothesized that bFGF plays a role in not only granulation tissue formation, but also re-epithelialization.Skin Research, Suppl. 17: 14-17, 2012

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Basic Fibroblast growth factor (bFGF, FGF-2) has been described as a multipotent cytokine that regulates cell growth as well as differentiation, matrix composition, chemotaxis, cell adhesion and migration in numerous cell types. It has traditionally been known that bFGF stimulates proliferation of cultured fibroblasts. However, the detailed mechanism of fibroblast growth by bFGF in vitro still remains to be elucidated. We investigated the precise effects of bFGF on the fibroblast proliferation and responsible signaling pathways for bFGF-induced proliferation in cultured human dermal fibroblasts (HDFs). In this study, bFGF increased the number of HDFs in a dose- and time-dependent manner. The bFGF-induced proliferation was suppressed by mitogen-activated protein kinase kinase (MEK) inhibitors, PD98059 or U0126, and JNK inhibitor, SP600125. bFGF increased the phosphorylation levels of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1. The treatment with ERK1, ERK2 or JNK1 siRNA significantly inhibited the bFGF-induced proliferation. In conclusion, ERK 1/2 and JNK pathways play an important role in the bFGF-mediated effect on HDFs.Skin Research, Suppl. 17: 18-26, 2012

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Human recombinant basic fibroblast growth factor (bFGF) has been available for the treatment for non-healing skin ulcer, however, there still exist unknown biological effects on wound healing. Recent clinical reports have pointed out bFGF promotes scarless wound healing. The mechanism, however, is still unclear. Previous our works have demonstrated that the down regulations of PI3K to Akt pathway and up regulation of Rho to Rho kinase pathway are involved in bFGF-promoted myofibroblast apoptosis. These facts indicate that bFGF can be a new therapeutic agent for the treatment of hypertrophic scar and keloid. Fibroblast-collagen matrix has been used as a model system to study how cells organize connective tissue. The current studies were carried out to elucidate the mechanism. In the present study, we harvested dermal fibroblasts from normal subjects and patients with keloid. 10ng/ml bFGF promoted stressed matrix contraction (SMC) on keloid fibroblasts but not normal fibroblasts. An further study was performed in order to elucidate the mechanism of SMC using three different kinase inhibitors: PI3K inhibitor, LY294002; Akt inhibitor and Rho kinase (ROCK) inhibitor, Y27632. Among three different inhibitors, only 10mM Y27632 was able to block the matrix contraction. The inhibitory effect was observed in cell spreading in the keloid-collagen gel, when they stimurated with 10ng/ml bFGF. Although a significant difference was not seen, 10ng/ml bFGF promoted apoptosis in keloid-fibroblasts but not in normal-fibroblasts even if two different inhibitors, LY294002 for phosphatidylinositol-3-Kinase and Akt inhibitor, were added. The present study implicates that bFGF has a possibility to have certain effects on keloid scars. Further studies are warranted to clarify the role of bFGF on keloid formation.Skin Research, Suppl. 17: 27-33, 2012

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We have already reported the immunohistochemical expression of fibroblast growth factor (FGF)-7 family protein in full-thickness skin wounds in hairless mice, which revealed that the FGF-7 family protein was localized in the superficial layers of the epidermis in the wound edge. In addition to the above-mentioned results, we reviewed the previous literatures concerning the localization of FGF families in skin wounds. Among the FGF families, FGF-7 mRNA was expressed in dermal fibroblasts, while FGF-2 protein was expressed in basal layer of reepithelialized epidermis. These results suggest that FGF family proteins have various localizations and functions in wound healing process.Skin Research, Suppl. 17: 34-38, 2012

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Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for post-transplant immunosuppression and treatment of autoimmune disease. Rapamycin inhibits mammalian target of rapamycin resulting in delayed wound healing. This delayed wound healing was normalized by treatment with basic fibroblast growth factor. This indicates that basic fibroblast growth factor plays an important and critical role in the rapamycin-induced delayed wound healing process.Skin Research, Suppl. 17: 39-44, 2012

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Derailment of normal wound healing processes is suspected in the pathogenesis of keloids and hypertrophic scars. Numerous treatment options have been described, but there is no single effective therapeutic regimen for the treatment of keloids. We investigated the anti scarring effect of basic fibroblast growth factor (bFGF) on keloids cells (KL cells) and normal dermal fibroblasts (Fb). In KL cells and Fb, the addition of bFGF inhibited the expression of type 1 collagen mRNA and enhanced the expression of MMP1 mRNA. These results suggested that the addition of bFGF suppressed the collagen deposition in keloids tissues and hypertrophic scars. This indicates that bFGF may have an anti scarring effect.Skin Research, Suppl. 17: 45-49, 2012

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