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    • Our results provide evidence that i transcription

    2018-11-02

    Our results provide evidence that (i) transcription factor NF-κB activation is necessary for limbal epithelial outgrowth on intact AM and MMP-9 expression (Fig. 4) and (ii) PI3-K/Akt and JNK pathways are involved in NF-κB activation (Figs. 5 and 6). Our data were supported by recent studies indicating that α6β4 signaling promotes epidermal growth and wound healing by controlling nuclear translocation of NF-κB and phosphorylation of JNK (Nikolopoulos et al., 2005). Accumulating evidence also suggests that NF-κB can be activated via the EGF receptor (Sun and Carpenter, 1998) and participate in the transcriptional control of cyclin D (Guttridge et al., 1999). Therefore, it is possible that transient activation of NF-κB (Fig. 5A) may be required for progression of limbal epithelial progenitor XL184 through the G1 phase of the cell cycle. Upregulation of MMP-9 depends on the activation of NF-κB and AP-1 which bind to the corresponding regulatory elements within the promoter region of the MMP-9 gene (Sato and Seiki, 1993). Unlike AP-1, which is common to many MMP promoters and is necessary for basal gene expression (Fini et al., 1994), NF-κB is responsible for activation of MMP-9 transcription (Liang et al., 2009). By use of a selective NF-κB inhibitor, Helenalin, we show that NF-κB is critically involved in MMP-9 regulation at both transcriptional and translational levels (Fig. 4B–D). Moreover, we also identified that PI3-K/Akt is upstream of the JNK pathway in activation of NF-κB and MMP-9 expression (Figs. 5B–D and 6). The finding that JNK1/2 phosphorylation was inhibited by LY294002 (Fig. 6D and E) may imply a crosstalk between these two pathways, as reported in another cell system (Aikin et al., 2004). Future studies are required to verify this hypothesis and identify the underlying mechanisms. Taken together, our findings support the hypothesis that divergent kinase activities regulate distinct cellular events associated with cell-cell matrix interactions such as in our model.
    Conclusions We demonstrate that both PI3-K/Akt and MAPK pathways provide the downstream signaling for outgrowth of limbal epithelial cells expanded on intact AM. Moreover, we also found that the expression of MMP-9 in this culture system is regulated via the PI3-K/Akt/JNK/NF-κB cascade. The relevant signaling network is depicted in Fig. 7. Further understanding of the molecular mechanisms underlying interactions between MMP-9 and other proteases as well as their crosstalk with specific growth factors (such as EGF) or adhesion molecules (such as integrins) would facilitate to formulate a new therapeutic strategy for corneal tissue engineering in the future.
    Materials and methods
    Acknowledgements We thank Dr. Chi-Chin Sun for providing the limbal tissues after conventional penetrating keratoplasty from human donor eyes. This work was supported by National Science Council (NSC96-2320-B-182-003 and NSC96-2320-B-182-047-MY3) and Chang Gung Medical Research Foundation (CMRPD32043 and CMRPD170332).
    Introduction Taurine is a sulfur amino acid, present in large amounts in most cell types and tissues as a free amino acid. It is not a protein amino acid and participates in only few metabolic reactions (Huxtable, 1992). Taurine has a function as osmoregulator (Pasantes-Morales, 2007) and exhibits a protective effect in a variety of detrimental situations, often acting as antioxidant (Schaffer et al., 2009). Early studies on brain taurine point to its involvement in brain development. Taurine levels in the immature brain are 3–4-fold higher than in the adult brain, a decrease consistently observed regardless of the species variations in brain taurine content (Agrawal et al., 1968; Sturman and Gaull, 1975; Miller et al., 2000). Taurine deficiency disturbs development in cats (Sturman, 1993) leading to a delay in cell division and migration in cerebellum and visual cortex (Sturman et al., 1985; Palackal et al., 1986). Similarly, taurine deprivation in newborn monkeys results in abnormalities in the visual cortex characterized by delayed migration of neurons and poor differentiation of pyramidal cells (Neuringer et al., 1990). Furthermore, studies in vitro in cultures of dissociated cerebellum showed that cell taurine depletion significantly reduces cell migration (Maar et al., 1995). It seems therefore that a deficiency of taurine disturbs the developmental precise program of cellular proliferation, migration and differentiation. In further support to an involvement of taurine in brain development, a recent study reports that the detrimental influence of gestational protein restriction on fetal brain is prevented by supplement of taurine during pregnancy (Liu et al., 2011).