Thus it appears that in the

Thus, it appears that in the adult SVZ, in the absence or low levels of Noggin, BMP proteins expressed by astrocytes and NSC bind and activate BMPR, presumably BMPR-1A, activating its downstream SMAD proteins. Activated SMADs up-regulate the expression of the miRNA coding gene Mirg which encodes miR-410. Higher levels of miR-410 then bind the transcripts of its targets: Elavl4, Sox1, Tcf4, Fgf7 and Smad7 decreasing their expression levels. Attenuated expression of Elavl4, and likely Sox1, then inhibit neuronal lineage differentiation. Down-regulation of Smad7 may further enhance Smad signal transduction, forming a positive feedback loop and strengthening lineage choice. Noggin, produced by the ependymal cells in the SVZ, binds BMP proteins, inhibiting downstream signaling, and reducing the expression of miR-410. The reduction in miR-410 may de-repress expression of its target genes, increases levels of Elavl4, which promotes neuronal differentiation of NSC. At the same time higher levels of Smad7 may further tune down BMP signaling through a positive feedback loop enhancing/reinforcing the neuronal fate decision. Our results (this work and our previous report (Morell et al., 2015)) support a model in which the majority of SVZ-derived oligodendrocytes form from cells at the transition between activated nociceptin receptor and C cells themselves (Parras et al., 2004; Menn et al., 2006). BMP signaling inhibits oligodendroglial differentiation, while antagonizing BMP signaling may recruit cells from the more committed Dlx2-positive C/A cell population (Colak et al., 2008) to the oligodendroglial lineage. However, in our previous report, over-expression of Noggin in the SVZ increased the numbers of both Mash1+ C cells and Olig2+ OPCs while the number of Dlx2/Oli2 double positive cells remained similar. Thus, it is unlikely the C cells are the major source of the OPCs. miR-410 acts directly downstream of BMP signaling to inhibit neurogenesis and oligodendrogenesis, although the molecular mechanisms controlling oligodendrogenesis requires further clarification. miR-410 has recently been suggested to be a prognostic marker in neuroblastoma (Gattolliat et al., 2011); patients with high miR-410 expression levels having higher survival rates. miR-410 also targets the hepatocyte growth factor receptor MET to regulate proliferation and invasion of glioma cells (Chen et al., 2012). We have observed that primary human glioblastoma cells express low levels of miR-410 (unpublished data), suggesting that miR-410, in addition to regulating lineage commitment, may also control proliferation and cancer stem cell behavior. However opposite functions have been reported in non-small cell lung cancer, as miR-410 appears to promote cell proliferation by targeting BRD7 in these cells (Li et al., 2015). Further clarification of miR-410 functions in different tissues and cells is of great importance and crucial to shed light on the multiple functions of miR-410. Overall, miR-410 may provide a new mechanism involved in the essential choice by NSC between self-renewal and differentiation. Further elucidation of miR-410 function may also identify novel approaches to the treatment of CNS injury and cancers.
Acknowledgements The authors gratefully acknowledge: Helen Zhang, Jack Parent, Dan Goldman and Roman Giger for advice and reagents, Martin Engelke for help with programming, Einor Jacobsen for Scholl analysis assistance, Ben Allen, Roger Tsien, and David Turner for plasmids. The work was supported by NIH grant NS-048187.
Introduction In the last year, significant efforts have been devoted to the identification of synthetic substrates able to support the expansion and/or differentiation of pluripotent stem cells. Biomaterials functionalized with stem cell niche-related proteins and/or pro-differentiating drugs could potentially be used to stimulate stem cell proliferation and differentiation within damaged or diseased regions of the body (Chandra and Lee, 2015; Vazin and Schaffer, 2010). However, the efficacy of their delivery for stimulating the generation and maturation of new differentiated cells may be limited either by the finite half-life of the proteins and by the drug kinetic release (Tong et al., 2015). Given the limited success of these approaches, strategies based on functional materials, such as various natural and synthetic polymers, have been proposed (Lutolf et al., 2009; Murphy et al., 2014). These artificial matrixes are able to accelerate stem cell expansion and differentiation without the addition of bioactive molecules. Several studies showed that polymers trigger biological responses through direct or synergistic interactions with cellular receptors, cytokines, or growth factors (Wang and Dong, 2015). Both polymers intrinsic (i.e. surface charge) and extrinsic properties (i.e. ability to interact with cells) played a pivotal role in dictating the type and strength of the biological responses. In particular, during the past two decades, cationic polymers have attracted tremendous attention for their application in regenerative medicine (Samal and Dubruel, 2015). Positive moieties can be provided by amino group in a variety of different forms (primary, secondary, tertiary and quaternary). The biomaterials containing quaternary amino groups, providing a permanent positive charge, have been the subject of extensive investigations in regenerative medicine, tissue engineering, and nanotechnology, due to their good hydrophilicity, high biocompatibility, and adequate chemical and thermal stability (Tabujew and Peneva, 2015).