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  • br Conclusion In this study we have

    2018-10-20


    Conclusion In this study we have successfully generated iPSCs, and iPSC-derived retinal organoids, from patients with TRNT1-associated RP and used these MLN 9708 to investigate the underlying pathophysiologic mechanisms of disease. We have also identified disease-specific phenotypes that provide new insight into how photoreceptor cells succumb in this disorder and that can be used as surrogate endpoints when testing the efficacy of novel gene based therapeutics. The following are the supplementary data related to this article.
    Disclosure of potential conflicts of interest
    Acknowledgements The authors wish to thank the patients and their families for their participation in this research study. This work was supported by The Stephen A. Wynn Foundation, National Institutes of Health (Grant # EY026008-02).
    Introduction NPY is a highly conserved 36-amino-acid neuropeptide that is broadly expressed in both the central and peripheral nervous systems (Allen et al., 1983; Tatemoto et al., 1982). NPY activates a group of six NPY G protein-coupled receptors (Y1R–Y6R), of which Y1R and Y2R are the most abundantly expressed in mammals (Movafagh et al., 2006; Lee et al., 2010; Teixeira et al., 2009). Previous studies have demonstrated that NPY regulates bone homeostasis through Y receptors expressed in bone marrow cells (Lee et al., 2010; Teixeira et al., 2009; Lee and Herzog, 2009; Liu et al., 2016), and NPY-deficient mice have significantly impaired bone marrow dysfunction, suggesting a protective role of NPY in the bone marrow microenvironment (Park et al., 2015). Researchers have also found that implanting sensory nerve tracts into tissue-engineered bone can significantly improve the early expression of Y1R and osteogenesis, and the same dramatic effect may be manifested by NPY through its stimulation of the proliferation, migration and differentiation of bone marrow stromal cells (BMSCs) (Park et al., 2015; Chen et al., 2010). At the same time, our previous studies reported that NPY stimulates osteoblastic differentiation and migration of BMSCs (Liu et al., 2016), and we observed that another neuropeptide, substance P, could regulate BMSC osteogenic differentiation, proliferation and apoptosis, thus promoting fracture healing (Fu et al., 2014, 2015). However, the proliferative effect of NPY on BMSCs is still controversial. NPY was reported to inhibit the proliferation of BMSCs, and BMSCs isolated from Y1−/− mice had a significantly greater proliferative ability than cultures isolated from wild-type mice (Lee et al., 2010). In contrast, other reports have suggested that NPY may stimulate the proliferation of BMSCs in vitro (Igura et al., 2011). Therefore, the specific role of NPY in proliferation and apoptosis of BMSCs, which are critical for maintaining an appropriate number of BMSCs in the body and play an important role in osteogenesis, has not been fully characterized and needs further study. A fast-growing field has linked the Wnt pathway with bone development, remodeling, and repair (Rawadi and Roman-Roman, 2005; Monroe et al., 2012; Westendorf et al., 2004). The best known Wnt signaling pathway involves β-catenin (commonly called the canonical pathway). Wnts are secreted glycoproteins that bind to receptor complexes such as low-density lipoprotein receptor-related protein (LRP) 5/6, which are disrupted and inhibit the activity of glycogen synthase kinase-3β (GSK-3β), these changes promote β-catenin translocation into the nucleus where it can regulate gene expression. Dickkopf-related protein-1 (DKK1) inhibits Wnt signaling by binding to LRP 5/6 and is considered a specific inhibitor of the canonical Wnt signaling pathway (Bafico et al., 2001). It has been shown that canonical Wnt signaling is a key player in the proliferation and survival of osteoblasts (Westendorf et al., 2004) and the proliferation and osteogenic differentiation of BMSCs, whereas DKK1 negatively regulates those effects (Gregory et al., 2005; Boland et al., 2004). However, the extent of canonical Wnt signaling participation in BMSC proliferation and apoptosis is still poorly understood.