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Y. Son, H. Hong, J. Kim; Identification of substance–p as an early inductive cytokine of corneal wound and its possible role in the mobilization of mesenchymal stem cell and corneal wound healing. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1423.
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Purpose:cornea wound seems to stimulate the release of several cytokines from surrounding epithelium, stroma, and sensory neurons, which constitutes unique wound microenvironment. Those cytokines and growth factors subsequently recruit cells from the neighboring tissue as well as stimulate mobilization of stem cells from the bone marrow. In this study, we first examined induction profile of cytokines and growth factors from the wound site and peripheral blood at different time after alkali burn on the mouse cornea by RT–PCR and Elisa. Substance–P was the earlist inductive cytokine at eye and peripheral blood. Then we investigated possible role of substance–p in the mobilization of mesenchymal stem cells (MSC) from the bone marrow and their participation in the wound healing.Methods:Alkali burn was induced on the mouse cornea. Wound site and blood were collected at different time after the wound. RT PCR was performed with primers of beta–actin as control, VEGF, VEGFR, SCF, substance–p, TNF–alpha, PIGF, IL–1, and HIF–1alpha. Elisa was also performed. MSCs were incubated with 1, 10, 100 nM substance–p for 16 h and induction pattern of MMPs, TIMPs, beta–catenin, VEGF, and fibronectin was examined by immunofluorescence staining, gelatin zymography, and Elisa Results: ; substance–P, SCF, IL–1 were markedly induced between day 1 and 5 after alkali burn at eye as well as peripheral blood by RT PCR and Elisa. Among them substance–p was prominent early inducer and peaked between day 1 and 3 post wound. VEGF was also induced but induction was after 5 day post wound. We explored the possible role of substance–p in the mobilization of MSCs from the bone marrow. Substance–P stimulated cell growth and nuclear localization of beta catenin in a dose dependent manner at the range of 1–100 nM. Substance–p 1 nM was sufficient enough to stimulate the secretion of MMP–2,9 and other unknown gelatin–zymographic bands and inhibited the induction of TIMP–1, which will create more favorable environment for the migration and mobilization of MSCs from the bone marrow. We are further evaluating roles of substance–p in the out–routing of MSCs from the marrow to the blood by i.v. injection of substance–p as well as in vitro migration assay Conclusions:We found that substance–p is the early cytokine induced by alkali burn wound and stimulate cell proliferation and mobilization of MSC, which suggest that it may play a messenger role in the mobilization and recruitment of stem cells residing at the marrow to the wound area.
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