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  • Introduction Previous studies describing functional recovery


    Introduction Previous studies describing functional recovery following transplantation of neural stem/progenitor EZ Cap Reagent AG (3\' OMe) (NS/PCs) in spinal cord injury (SCI) models demonstrated the therapeutic promise of this approach (Cummings et al., 2005; Iwanami et al., 2005). A number of putative underlying mechanisms have been suggested, including cell replacement by grafted NS/PC-derived neurons, astrocytes, and oligodendrocytes; trophic support for increased survival of the host neural cells and host-mediated repair processes; and, more recently, axonal remyelination by grafted NS/PC-derived oligodendrocytes (Cummings et al., 2005; Keirstead et al., 2005; Salewski et al., 2015; Yasuda et al., 2011). Human NS/PCs and human-induced pluripotent stem cell-derived NS/PCs (hiPSC-NS/PCs) predominantly differentiate into neurons, and, to a lesser extent, into mature oligodendrocytes both in vitro and in vivo (Kobayashi et al., 2012; Nori et al., 2011, 2015; Romanyuk et al., 2015). We therefore developed a protocol for the induction of oligodendroglial differentiation of hiPSC-NS/PCs in vitro (Numasawa-Kuroiwa et al., 2014). In the present study, we used a pre-evaluated safe line of induced pluripotent stem cells (iPSCs; 201B7) (Nori et al., 2011, 2015) and induced their differentiation into oligodendrocyte precursor cell-enriched NS/PCs (hiPSC-OPC-enriched NS/PCs). The aim of this study was to evaluate the therapeutic potential of hiPSC-OPC-enriched NS/PCs in the treatment of SCI.
    Experimental Procedures
    Acknowledgments We thank Prof. Shinya Yamanaka for the human iPSC clones (201B7). This work was supported by grants from the Japan Science and Technology-California Institute for Regenerative Medicine Collaborative Program; Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (SPS) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT); and a grant for the Research Center Network for Realization of Regenerative Medicine from the A-MED to H.O. H.O. is a founding scientist and a paid SAB of San Bio, Co., Ltd. The other authors indicated no potential conflicts of interest.
    Introduction Age-related macular degeneration (AMD), the most common cause of severe vision loss in the Western world, occurs in wet (neovascular) and dry (degenerative) forms. In early dry AMD, the retinal pigment epithelium (RPE) becomes dysfunctional, whereas end-stage disease, geographic atrophy (GA), is characterized by degeneration of RPE and photoreceptors (Bhutto and Lutty, 2012). The RPE is a monolayer of polarized cells that constitutes the outer blood-retina barrier and performs central tasks in the eye, e.g., light adsorption, secretion of growth factors, and phagocytosis of photoreceptor outer segments (POS) (Sparrow et al., 2010). The apical surface harbors microvilli that interact with the light-sensitive POS, whereas the basolateral surface adheres to Bruch\'s membrane (BM), which in turn separates the RPE from the underlying choroid. Subretinal transplantation of RPE cells derived from human embryonic stem cells (hESC) could potentially be used as replacement therapy in GA (Schwartz et al., 2012, 2015). However, a critical question is whether donor cells integrate into the host RPE and support the overlying photoreceptors. Experimental transplantations of hESC-RPE have only been conducted in small-eyed rodent models (Carido et al., 2014; Idelson et al., 2009; Lund et al., 2006; Vugler et al., 2008). Functional effects in these models are however non-specific and surgical techniques, instrumentation, and imaging methods differ from those applied in humans, limiting their use as preclinical models (e.g., Pinilla et al., 2009). We have recently described a damage model in the large-eyed rabbit that exhibits typical GA changes including photoreceptor loss and RPE alterations (Bartuma et al., 2015). Several hESC-RPE derivation protocols have been described with the common limitation of relying on culture steps that involve xeno- or human-feeder cells or use medium components that are either undefined or not xeno-free (Klimanskaya et al., 2004; Lane et al., 2014; Osakada et al., 2009; Pennington et al., 2015; Vaajasaari et al., 2011). Recently, we described a defined and xeno-free clonal culture of hESC using recombinant human laminin (rhLN) and E-cadherin (Rodin et al., 2014a, 2014b). Encouraged by this work, we set out to evaluate whether rhLN-matrix could support efficient hESC-RPE differentiation. BM, the RPE basement membrane, contains four LNs, LN-111, LN-332, LN-511, and LN-521, that adhere to the RPE via specific integrins (Aisenbrey et al., 2006).