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  • Taken together our findings support the hypothesis


    Taken together, our findings support the hypothesis that AM can rescue OPC differentiation via receptor-mediated Akt signaling. However, there are some important caveats to keep in mind. First, our current study used only a pure cell culture system. However, to prove clinically-relevant supportive/protective roles of AM on OPCs against stress, we should test the efficacy of AM on in vivo white matter injury animals. Second, our data indicate that short-term AM treatment was not supportive for in vitro OPC differentiation under pathological conditions. A single treatment of AM could activate the downstream pathway (i.e. Akt phosphorylation), but to sufficiently drive the OPC differentiation, multiple rounds of AM treatments would be required. Before testing the efficacy of AM using in vivo animal models, further investigation into the underlying mechanisms of AM/Akt-induced OPC maturation is needed to identify effective treatment schedules of AM. Third, we only examined the PI3K/Akt pathway as an intracellular signaling pathway for in vitro oligodendrogenesis by AM. But the AM receptor would activate other cellular signaling pathways, such as MEK/ERK or cAMP/PKA pathways (Nagaya et al., 2005). Whether these pathways are also involved in the OPC-supportive effects of AM should be carefully examined in future studies. Finally, as OPCs are generated from NSPCs, we may also need to test if AM can enhance the number of newly generated OPCs from NSPCs after white matter injury. A recent study showed that lack of AM results in profound changes in the proliferation and differentiation rates in the progeny of NSPCs isolated from the olfactory bulbs of AM deficient mice. NSPCs derived from the AM deficient mice produced a lower proportion of neuronal-astroglial lineage apexbio dilution and a higher proportions of oligodendrocyte lineage cells compared to NSPCs from WT mice (Vergano-Vera et al., 2010). Hence, future studies are warranted to examine how AM regulates the cell fates of NSPCs under normal and pathological conditions. The following are the supplementary data related to this article.
    Funding information Supported in part by the National Institutes of Health (P01 NS055104, R01 NS065089), Research Abroad from the Uehara Memorial Foundation (201340190), and the Japan Society for the Promotion of Science. We thank Dr. Noriko Osumi for the many helpful discussions.
    Introduction Cholesterol is an essential structural component of the cell membrane and is needed for cell shape and motility. Cholesterol is also an important source for the production of steroid hormones such as the glucocorticoids (Gcrt), mineralocorticoids (Mnrt), estrogen and testosterone, which are produced by a series of cytochrome class enzymes (Han et al., 2014). Interestingly, very little is known about the function of cholesterol derivatives during early mammalian development, despite the fact that the two cholesterol modifying enzymes Cyp11a1 and Cyp17a1 are prominently expressed and active in the visceral endoderm of gastrulating mouse embryos (Bair and Mellon, 2004; Korgun et al., 2003). Moreover, Cyp17a1 is essential for early development since deletion of the Cyp17a1 gene in the mouse results in death by embryonic day 7 (Bair and Mellon, 2004). In addition, mRNA for the receptor Nr3c1 of the cholesterol-derived Gcrt is enriched in the endoderm of the rat embryo (Korgun et al., 2003). Gcrts comprise a class of steroid hormones that are important for adult life (Kadmiel and Cidlowski, 2013; Newton, 2000). Synthetized in the adrenal cortex of adults, Gcrts reach most organs through the bloodstream. Once within cells, Gcrts bind to the nuclear receptor Nr3c1, causing receptor dimerization and translocation to the nucleus, where the ligand–receptor complex interacts with Gcrt response elements in the promoters of Gcrt target genes (Kadmiel and Cidlowski, 2013; Newton, 2000). Functionally, Gcrts are best known for maintaining glucose levels in adults, thereby providing a steady supply of ATP and pyruvate, both essential energy components for the cell. Gcrts are also important repressors of inflammation through a negative feedback loop of the immune system (Kadmiel and Cidlowski, 2013; Newton, 2000). Very little is known about Gcrt function during early mammalian embryonic development, and to our knowledge, a role in cell fate specification is unexplored.