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• W2035968100 abstract "A major question in studying adult neurogenesis is the source and identity of molecules that regulate stem cells. In this issue of Neuron, Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar uncover that endothelial-derived NT-3 acts as a mediator of quiescence in the V-SVZ adult neural stem cell niche. A major question in studying adult neurogenesis is the source and identity of molecules that regulate stem cells. In this issue of Neuron, Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar uncover that endothelial-derived NT-3 acts as a mediator of quiescence in the V-SVZ adult neural stem cell niche. Neural stem cells persist in specialized niches in the adult mammalian brain. Stem cells in the ventricular/subventricular zone (V/SVZ), also known as the subependymal zone (SEZ), which is located adjacent to the lateral ventricles, give rise to neurons that migrate to the olfactory bulb (Figure 1A). Interestingly, V/SVZ stem cells share ultrastructural and molecular features of astrocytes. Upon activation, glial fibrillary acidic protein (GFAP)-positive quiescent neural stem cells (qNSCs) upregulate markers of proliferation, as well as epidermal growth factor receptor (EGFR) and nestin (Codega et al., 2014Codega P. Silva-Vargas V. Paul A. Maldonado-Soto A.R. Deleo A.M. Pastrana E. Doetsch F. Neuron. 2014; 82: 545-559Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). They then generate rapidly dividing transit-amplifying cells, which in turn give rise to neuroblasts that migrate to the olfactory bulb (Figure 1B). A small number of oligodendrocytes are also generated in the V/SVZ. The adult V/SVZ stem cell niche is complex. Two essential compartments are the cerebrospinal fluid (CSF) and a specialized vasculature. V/SVZ stem cells (B1 cells) have an elongated radial morphology and span all compartments of the niche. The apical process of B1 cells contacts the CSF, which flows dynamically through the lateral ventricles. The primary source of the CSF is the choroid plexus, a highly vascularized miniorgan that floats in each ventricle. B1 cells also extend a long basal process that contacts the planar vascular plexus in the SVZ (Figure 1A). As such, B1 stem cells are exposed to diverse signals, including cell-cell and extracellular matrix interactions, and diffusible signals from different sources, which they integrate to regulate their behavior (reviewed in Silva-Vargas et al., 2013Silva-Vargas V. Crouch E.E. Doetsch F. Curr. Opin. Neurobiol. 2013; 23: 935-942Crossref PubMed Scopus (104) Google Scholar). How different niche compartments affect each stage of the stem cell lineage is just beginning to emerge. Recent work has highlighted that the quiescent state is actively maintained. Cell adhesion plays a key role in neural stem cell quiescence. Disrupting cell-cell or cell-ECM contacts leads to increased proliferation of neural stem cells (reviewed in Silva-Vargas et al., 2013Silva-Vargas V. Crouch E.E. Doetsch F. Curr. Opin. Neurobiol. 2013; 23: 935-942Crossref PubMed Scopus (104) Google Scholar). In addition, ligands present in the CSF, such as S1P and PGD2, also actively maintain stem cell quiescence (Codega et al., 2014Codega P. Silva-Vargas V. Paul A. Maldonado-Soto A.R. Deleo A.M. Pastrana E. Doetsch F. Neuron. 2014; 82: 545-559Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). In contrast, diffusible signals from endothelial cells, including SDF1 and PEDF, promote the proliferation of activated stem cells and transit-amplifying cells (reviewed in Silva-Vargas et al., 2013Silva-Vargas V. Crouch E.E. Doetsch F. Curr. Opin. Neurobiol. 2013; 23: 935-942Crossref PubMed Scopus (104) Google Scholar). In this issue of Neuron, Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar show a novel role for endothelial-derived neurotrophin-3 (NT-3), a member of the neurotrophin family classically associated with cell survival, in mediating neural stem cell quiescence in the adult neurogenic niche. High levels of NT-3 are made by discrete populations of neurons and astrocytes in the nervous system. Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar show that NT-3 is also produced, at lower levels, by brain endothelial cells and by the microvasculature in the choroid plexus. Notably, NT-3 protein is also found in the CSF. Conditional deletion of NT-3 in endothelial cells leads to the loss of NT-3 protein in both the V/SVZ and CSF, confirming that endothelial cells are a major source of NT-3 in V/SVZ stem cell niche. B1 cells and ependymal cells do not synthesize NT-3. B1 cells express both TrkB and TrkC receptors, but not TrkA, and take NT-3 up from the microenvironment. To functionally assess the role of NT-3, Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar used several approaches to manipulate NT-3 levels. First, they investigated proliferation in B1 cells in young adult (60-day-old) heterozygous NT-3 mutants and found that the proportion of dividing GFAP+ B1 cells, as well as of label retaining cells, is increased, with no change in the total proportion of GFAP+ cells. This increase was accompanied by higher numbers of olfactory bulb neurons and significant changes in olfactory behavior. An increase in oligodendrocyte formation was also observed. However, fate-mapping studies will be needed to dissect whether the changes in oligodendrocyte formation are due to increased stem cell proliferation or alternatively to increased proliferation of NG2+ progenitors in the corpus callosum due to local changes in NT-3 in the white matter (Kahn et al., 1999Kahn M.A. Kumar S. Liebl D. Chang R. Parada L.F. De Vellis J. Glia. 1999; 26: 153-165Crossref PubMed Scopus (87) Google Scholar). Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar also examined neurosphere formation as a functional in vitro assay to assess stem cells. In heterozygous NT-3 mice, an increased number of neurospheres formed as compared to wild-type mice, with no change in the size of individual neurospheres, consistent with an expanded pool of actively dividing cells in vivo that give rise to neurospheres (Pastrana et al., 2011Pastrana E. Silva-Vargas V. Doetsch F. Cell Stem Cell. 2011; 8: 486-498Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar). The same effect was observed when SVZ cells were cultured with conditioned medium from endothelial cells or in transwells with primary brain endothelial cells in which NT-3 was conditionally deleted from endothelial cells using Tie2-Cre as a driver. Conversely, NT-3 treatment of wild-type SVZ cells decreased neurosphere formation and was reversed by blocking with TrkC antibodies. Interestingly, after the initial proliferative burst in young adult mice, in heterozygous NT-3 middle-aged mice (240 days old), neurosphere formation and LRCs both decreased, suggesting that over time, B1 stem cells become depleted. At this time point, there was also an increase in GFAP+S100+ cells, suggesting that increased astrocytic differentiation might be occurring as well. Altogether, these results elegantly demonstrate that endothelial-derived NT-3, either from the V/SVZ vasculature or in the CSF, exerts a cytostatic effect in the SVZ stem cell niche. How are the effects of endothelial-derived NT-3 mediated? Nitric oxide (NO) is a gaseous signaling molecule that is synthesized by the enzyme nitric oxide synthase (NOS), which catalyzes the conversion of L-arginine and oxygen into citrulline and NO. There are three isoforms of NOS in the brain, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS. nNOS is expressed by nitrergic neurons in close proximity to the SVZ (Figure 1A). Under physiological conditions, NO inhibits proliferation in adult neurogenic niches in both SVZ and SGZ but after injury has the opposite effect and increases proliferation (Estrada and Murillo-Carretero, 2005Estrada C. Murillo-Carretero M. Neuroscientist. 2005; 11: 294-307Crossref PubMed Scopus (62) Google Scholar, Berg et al., 2013Berg D.A. Belnoue L. Song H. Simon A. Development. 2013; 140: 2548-2561https://doi.org/10.1242/dev.088005Crossref PubMed Scopus (154) Google Scholar). In pulmonary and brain vasculature, NT-3 regulates the levels of eNOS. Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar therefore hypothesized that the production of NO could be mediating the cytostatic effect of NT-3 on SVZ cells and tested this using a combination of genetic and pharmacological approaches in their coculture system of endothelial and SVZ cells. L-NAME, a general NOS inhibitor, increased neurosphere formation by SVZ cells cocultured with endothelial cells; this effect was reversed by cotreatment with NT-3. In contrast, treatment with an nNOS-specific inhibitor had no effect. By mixing and matching SVZ cells and endothelial cells of opposite eNOS genotypes (mutant or wild-type eNOS), they showed that eNOS acts cell autonomously in SVZ cells and that in SVZ cells, eNOS is rapidly phosphorylated, leading to an increased synthesis of NO upon NT-3 treatment or culture with endothelial conditioned medium. Finally, Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar confirmed that CSF-borne NT-3 could access B1 cells. In vivo infusion of NT-3 into the lateral ventricle decreased proliferation of GFAP+ cells in vivo and rescued the increased proliferation in Ntf3-Tie2ko mice, but had no effect when infused into the lateral ventricle of eNOS mutant mice. Together, these experiments show that endothelial-derived NT-3 acts as a cytostatic factor for SVZ cells via an eNOS-dependent pathway. Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar clearly demonstrate that endothelial-derived NT-3 inhibits proliferation of GFAP+ B1 cells in vivo and decreases neurosphere formation in vitro. However, although widely used, neurospheres are not an ideal readout of in vivo stem cells (Pastrana et al., 2011Pastrana E. Silva-Vargas V. Doetsch F. Cell Stem Cell. 2011; 8: 486-498Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar). First, both EGFR+-activated neural stem cells and transit-amplifying cells give rise to neurospheres. Moreover, new fluorescence-activated cell sorting (FACS) purification strategies have recently allowed the prospective isolation of quiescent neural stem cells for the first time (Codega et al., 2014Codega P. Silva-Vargas V. Paul A. Maldonado-Soto A.R. Deleo A.M. Pastrana E. Doetsch F. Neuron. 2014; 82: 545-559Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar, Mich et al., 2014Mich J.K. Signer R.A. Nakada D. Pineda A. Burgess R.J. Vue T.Y. Johnson J.E. Morrison S.J. Elife (Cambridge). 2014; 3: e02669Google Scholar). In contrast to aNSCs, qNSCs largely do not give rise to neurospheres but only do so upon activation and upregulation of EGFR and nestin (Codega et al., 2014Codega P. Silva-Vargas V. Paul A. Maldonado-Soto A.R. Deleo A.M. Pastrana E. Doetsch F. Neuron. 2014; 82: 545-559Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar; Figure 1B). Interestingly, NO inhibits both EGFR and PI3K signaling in SVZ cells (Torroglosa et al., 2007Torroglosa A. Murillo-Carretero M. Romero-Grimaldi C. Matarredona E.R. Campos-Caro A. Estrada C. Stem Cells. 2007; 25: 88-97Crossref PubMed Scopus (118) Google Scholar). As such, in the future, it will be very important to use FACS-purified populations instead of bulk SVZ cells to define the effect of NT-3 and other niche factors on each stage in the stem cell lineage, including qNSCs, aNSCs, and transit-amplifying cells both in vivo and in vitro, given the key role of EGFR in this region. Indeed, this will allow the precise dissection of whether NT-3 is acting to increase neurosphere formation by (1) recruiting more quiescent neural stem cells to an activated state (light blue) that are able to form neurospheres, (2) changing the proliferation rates or modes of division (filled ovals) of aNSCs, thereby increasing their capacity to form neurospheres, and/or (3) changing the proliferation rates or modes of division of transit-amplifying cells (green-filled ovals) to increase their neurosphere formation (Figure 1E). Nitrergic neurons adjacent to the SVZ also synthesize NO and affect SVZ proliferation (Estrada and Murillo-Carretero, 2005Estrada C. Murillo-Carretero M. Neuroscientist. 2005; 11: 294-307Crossref PubMed Scopus (62) Google Scholar). As such, there are two different sources of NO, local neurons and the stem cells themselves (and probably transit-amplifying cells), highlighting the complexity of NO signaling in the niche. How these two NO-mediated pathways are integrated and whether they signal via different downstream cascades under different physiological conditions will be important to further explore. The CSF is a complex reservoir of signals from multiple sources, including systemic factors that may dynamically reflect the physiological state of the animal (Silva-Vargas et al., 2013Silva-Vargas V. Crouch E.E. Doetsch F. Curr. Opin. Neurobiol. 2013; 23: 935-942Crossref PubMed Scopus (104) Google Scholar). In the embryo, the CSF contains many proliferation signals (Lehtinen et al., 2011Lehtinen M.K. Zappaterra M.W. Chen X. Yang Y.J. Hill A.D. Lun M. Maynard T. Gonzalez D. Kim S. Ye P. et al.Neuron. 2011; 69: 893-905Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). In the adult, the CSF has been proposed to promote quiescence and the vasculature proliferation. The present paper by Delgado et al., 2014Delgado A.C. Ferrón S.R. Vicente D. Porlan E. Perez-Villalba A. Trujillo C.M. D’Ocón P. Fariñas I. Neuron. 2014; 83 (this issue): 572-585Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar shows that the endothelial compartment also contributes to maintaining quiescence in the adult SVZ stem cell niche. Given the regional heterogeneity among adult neural stem cells (Kriegstein and Alvarez-Buylla, 2009Kriegstein A. Alvarez-Buylla A. Annu. Rev. Neurosci. 2009; 32: 149-184https://doi.org/10.1146/annurev.neuro.051508.135600Crossref PubMed Scopus (1631) Google Scholar), as well as in the niche, it will be very interesting to determine whether the effect of NT-3, or other niche factors, is selective for a regional subset of V/SVZ stem cells, how regional differences in the niche impact in vivo regulation, and how these both change during aging. The cellular and molecular dissection of the contribution of different niche compartments to adult neural stem cell regulation is ready to be cracked open and will illuminate how diffusible and contact mediated signals from the vascular niche, cerebrospinal fluid, and other niche elements are integrated and eventually can be harnessed for brain repair. Endothelial NT-3 Delivered by Vasculature and CSF Promotes Quiescence of Subependymal Neural Stem Cells through Nitric Oxide InductionDelgado et al.NeuronJuly 17, 2014In BriefAdult neural stem cells reside and proliferate in perivascular/periventricular niches. Delgado et al. show that the cells can regulate their own quiescence and maintenance through nitric oxide generation but this requires exposure to endothelium-derived neurotrophin-3 present in vasculature and cerebrospinal fluid. Full-Text PDF Open Archive" @default.
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• W2035968100 title "A New Twist for Neurotrophins: Endothelial-Derived NT-3 Mediates Adult Neural Stem Cell Quiescence" @default.
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