Neural stem cell transplantation is currently investigated a

Neural stem cell transplantation is currently investigated as a treatment for different CNS injuries and disorders. One key challenge for a successful cell therapy is that an inflammatory environment in the diseased CNS might trigger glial differentiation of transplanted NSCs or NPCs (Aboody et al., 2011; Reekmans et al., 2012; Robel et al., 2011). Additionally, there might be a safety concern on the oncogenic potential of human iPSC-derived NSCs. Previous studies on BET bromodomain inhibition have demonstrated profound anti-proliferative and anti-inflammatory effects (Belkina and Denis, 2012). Our study provided new evidence on a dual role of BET inhibition in promoting neurogenesis and suppressing gliogenesis. Together it suggests a potential clinical application of I-BET in neural stem cell therapy for enhanced efficacy and improved safety in cell-based transplantation. The following are the supplementary data related to this article.
Acknowledgements
Introduction Intracellular and extracellular mechanisms combine to maintain the neurogenic niches in the adult annexin v (review, (Ming and Song, 2011)). In fact, considerable work has demonstrated that dynamic interactions between these compartments regulate cell behaviors within the germinal niche and ultimately its neuronal vs glial output. In addition to transcriptional regulators, intracellular modulators including non-coding microRNAs have been shown to control proliferation, self-renewal and cell fate choice in the nervous system via their ability to bind and inhibit translation or to promote degradation of critical target genes (Gangaraju and Lin, 2009). Cell type-specific microRNAs (He et al., 2012; Jovicic et al., 2013) which bind and suppress lineage specifying genes or groups of genes, are thought to play a critical role in maintaining the niche and controlling differentiation. For example, one of the most abundant microRNAs in the CNS, miR-124, is up-regulated at the transition from subventricular zone (SVZ) transit amplifying C cells to neuroblasts (A cells), thereby promoting neurogenesis (Bian and Sun, 2011; Bian et al., 2013b; Bian et al., 2013a). Regulatory networks are beginning to be identified—i.e., miR-25 can promote proliferation of neural stem cells (NSC) via its ability to regulate the IGF signaling pathway (Brett et al., 2011), while Sox2 regulates miR-137, which in turn targets Ezh2 to inhibit differentiation and promote NSC proliferation (Szulwach et al., 2010). Although many genes and epigenetic mechanisms that regulate miRNAs have been identified (Ji et al., 2013), the extracellular regulation of miRNAs, particularly within the CNS, has been less well studied. Despite the potential importance of microRNAs in understanding CNS development (Lang and Shi, 2012), disease (Eacker et al., 2009), in identifying molecular markers (Di Leva and Croce, 2013), and potentially in therapeutic approaches (Pers and Jorgensen, 2013), the critical link between the extracellular compartment and microRNA expression and function is poorly understood (Bian et al., 2013a). In a previous paper (Morell et al., 2015), we describe a transgenic mouse in which expression of the BMP signaling pathway inhibitor, Noggin, in SVZ NSC promotes neuronal and oligodendroglial differentiation, while decreasing astrocyte differentiation both in vivo and in vitro. Microarray analysis of RNAs from Noggin over-expressing and control SVZs identified a microRNA, miR-410, which was down-regulated with BMP pathway inhibition. We have determined that miR-410 is expressed in the SVZ NSC niche, and transiently in mESC as they differentiate into neurons, where it inhibits neuronal differentiation and can reverse the noggin-stimulated increase in neuronal differentiation. Predicted targets of miR-410: Elavl4, Sox1, Smad7, Tcf4 and Fgf7 were validated in luciferase assays, and expression of Elavl4 rescued the inhibitory effects of miR-410 on neuronal differentiation, providing an additional mechanistic link between BMP signaling and neurogenesis. Unexpectedly, miR-410 also affected process outgrowth and neuronal morphologies.