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• W2038231738 abstract "Identifying multipotent, self-renewing neural stem cells (NSCs) within the adult hippocampus in vivo has been somewhat elusive. In this issue of Cell Stem Cell, Suh et al., 2007Suh H. Consiglio A. Ray J. Sawai T. D'Amour K.A. Gage F.H. Cell Stem Cell. 2007; 1 (this issue): 515-528Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar show that Sox2-expressing cells in the subgranular zone (SGZ) of the dentate gyrus not only have NSC characteristics but also display an unexpected degree of heterogeneity. Identifying multipotent, self-renewing neural stem cells (NSCs) within the adult hippocampus in vivo has been somewhat elusive. In this issue of Cell Stem Cell, Suh et al., 2007Suh H. Consiglio A. Ray J. Sawai T. D'Amour K.A. Gage F.H. Cell Stem Cell. 2007; 1 (this issue): 515-528Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar show that Sox2-expressing cells in the subgranular zone (SGZ) of the dentate gyrus not only have NSC characteristics but also display an unexpected degree of heterogeneity. A tenet of the adult stem cell niche hypothesis asserts that the tissue microenvironment regulates the cell cycle, self-renewal, and multilineage potential of stem cells. This principle leads to the widely accepted corollary that stem cells removed from their niche display cellular behaviors that may not be indicative of their normal function in vivo. In other words, it is the difference between what stem cells can do and what they normally do. For example, stem cells in vitro often display broader proliferative capacity, or can generate specific cell types in proportions that are different than those produced in vivo. Nonetheless, the peculiarities of niche-independent stem cell behavior can, to some extent, be rationalized by the notion that the niche necessarily mitigates a full stem cell repertoire in vivo due to physiological constraints. In the adult vertebrate brain, neurogenic compartments display a strong bias in the types of cells that are generated (usually neuron production dominates), and the putative NSCs in these regions are thought to divide infrequently. Thus, it is difficult to define the in vivo identity of adult NSCs based on correlations of in vitro and in vivo behaviors. This challenge is exemplified in studies of hippocampal neurogenesis. Previously, in vitro experiments showed that multipotent, self-renewing NSCs could be isolated from the adult hippocampus, supporting the model that these NSCs resided in the SGZ, where neurogenesis normally occurs (Gage et al., 1998Gage F.H. Kempermann G. Palmer T.D. Peterson D.A. Ray J. J. Neurobiol. 1998; 36: 249-266Crossref PubMed Scopus (608) Google Scholar). However, at the time, direct in vivo evidence of NSCs within the SGZ was lacking. Indeed, recent studies challenged this model (Seaberg and van der Kooy, 2002Seaberg R.M. van der Kooy D. J. Neurosci. 2002; 22: 1784-1793PubMed Google Scholar, Bull and Bartlett, 2005Bull N.D. Bartlett P.F. J. Neurosci. 2005; 25: 10815-10821Crossref PubMed Scopus (202) Google Scholar). Microdissection of distinct hippocampal-associated regions demonstrated that, although the adult dentate gyrus contained progenitor cells capable of clonal proliferation in vitro, these cells were only transiently self-renewing and separately specified to neuronal or glial fates. In contrast, clonally derived colonies from cells isolated from the surrounding periventricular subependyma displayed multilineage potential and longer-term self-renewal in vitro. Furthermore, pyramidal neurons in the hippocampal CA1 region are partially regenerated from periventricular subependymal NSCs postischemia (Nakatomi et al., 2002Nakatomi H. Kuriu T. Okabe S. Yamamoto S. Hatano O. Kawahara N. Tamura A. Kirino T. Nakafuku M. Cell. 2002; 110: 429-441Abstract Full Text Full Text PDF PubMed Scopus (1251) Google Scholar). These studies supported an alternative model, whereby quiescent NSCs reside in the surrounding subependymal regions of the hippocampus but neuronal and glial progenitor cells with limited proliferation mediate persistent neurogenesis in the dentate gyrus. Now, Suh et al., 2007Suh H. Consiglio A. Ray J. Sawai T. D'Amour K.A. Gage F.H. Cell Stem Cell. 2007; 1 (this issue): 515-528Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar provide a significant advancement toward resolving whether the SGZ harbors NSCs. Based on previous studies showing that the transcriptional regulator Sox2, together with other SoxB1 class genes, was required for maintaining embryonic NSC identity and self-renewal (Bylund et al., 2003Bylund M. Andersson E. Novitch B.G. Muhr J. Nat. Neurosci. 2003; 6: 1162-1168Crossref PubMed Scopus (605) Google Scholar, Graham et al., 2003Graham V. Khudyakov J. Ellis P. Pevny L. Neuron. 2003; 39: 749-765Abstract Full Text Full Text PDF PubMed Scopus (941) Google Scholar), the authors hypothesized that the expression of Sox2 would define the most primitive progenitor cells (possibly the NSCs) within the adult SGZ. Using a Sox2:gfp transgenic mouse, Suh et al. reveal that GFP+ cells within the SGZ of the dentate gyrus are undifferentiated and express makers indicative of NSCs, such as BLBP and Musashi-1. Two classes of GFP+ cells were identified: a radial-glia-like cell expressing additional stem cell markers GFAP and Nestin, and a nonradial cell with no demonstrable expression of these two markers. Interestingly, only the nonradial cells showed signs of in vivo proliferation, suggesting that the radial GFP+ cells either had a much longer cell-cycle time or were postmitotic. In vitro, clonally derived undifferentiated GFP+ cells proliferated extensively and were capable of multilineage differentiation. However, it was not determined whether NSCs within the periventricular subependyma surrounding the hippocampus also expressed the Sox2:gfp transgene and whether they were co-isolated in these experiments. Nonetheless, given that most of the GFP+ cells reside within the SGZ, these data indicate that Sox2-expressing cells in this compartment behave as NSCs in vitro. The crucial question was whether the GFP+ cells displayed similar NSC behaviors in vivo. A genetic recombination strategy was used to provide an indelible genetic marker for tracking lineal relationships among newborn cells. A Sox2 promoter was used to drive the expression of a GFP-Cre recombinase fusion protein that was delivered by lentivirus directly to the dentate gyrus cells in ROSA26 reporter mice. The authors demonstrated that the vast majority of proliferating Sox2-expressing cells gave rise to differentiated neurons, while a smaller percentage of proliferating cells maintained their undifferentiated phenotype or differentiated into astrocytes. Collectively, these data indicate that the Sox2-expressing cells within the SGZ, as a population, are able to self-renew and generate neurons and astrocytes. Because lentivirus transduction can occur in committed progenitors that have exited the cell cycle, but still express Sox2, these observations do not completely rule out the possibility that separate subpopulations of SOX2+ cells in the SGZ normally give rise to neurons and astrocytes. Thus, the authors asked whether single SOX2+ cells could generate both neurons and astrocytes by using a similar GFP-Cre fusion construct, except this time by retroviral delivery at limiting dilution, which unlike the lentivirus can only be incorporated into cells that are dividing at the time of delivery (likely the nonradial, undifferentiated cells). Most clones contained single neurons or single astrocytes, whereas multicellular clones were composed mostly of only SOX2+ cells or only neurons. One clone contained a neuron and astrocyte, whereas a separate clone contained one neuron and a radial undifferentiated SOX2+ cell. These data highlight the fact that, in vivo, NSCs in the SGZ are heavily biased to generate neurons. However, at least a subset of SOX2+ SGZ cells retains their multipotentiality in vivo, in addition to a substantial self-renewal capacity. Once again, the niche appears to constrain NSC behavior. Surprisingly, the cells actively displaying these hallmark features of NSCs in vivo were not radial-glial like, as was previously suggested (Seri et al., 2004Seri B. Garcia-Verdugo J.M. Collado-Morente L. McEwen B.S. Alvarez-Buylla A. J. Comp. Neurol. 2004; 478: 359-378Crossref PubMed Scopus (504) Google Scholar). However, when animals were challenged in a running paradigm, both nonradial and radial Sox2-expressing cells increased their proliferation and gave rise to new neurons in the dentate gyrus, indicating that NSCs in the SGZ can respond directly to physiologically salient cues to modify the rate of neuronal production. One question to emerge is whether there is a continual lineage relationship between the two types of NSCs within the adult dentate gyrus. The authors propose that radial cells represent a relatively quiescent (and inducible) subpopulation of neural stem cells, whereas the nonradial NSCs play a more active role in maintenance of homeostatic levels of neurogenesis. This would suggest the intriguing possibility that the heterogeneity of morphological states of NSCs are interchangeable based on the cell cycle, rather than directional based on the stage of lineage development. However, more detailed lineage and cell-cycle experiments are needed to resolve these alternative models of NSC heterogeneity within the SGZ. The stem cell niche model is a useful concept for not only delineating the broad differences in the overall profile of neurogenesis between compartments but also for helping us formulate questions about the regulative relationship among the cell types within a single compartment (Doetsch, 2003Doetsch F. Curr. Opin. Genet. Dev. 2003; 13: 543-550Crossref PubMed Scopus (519) Google Scholar, Ninkovic and Gotz, 2007Ninkovic J. Gotz M. Curr. Opin. Neurobiol. 2007; 17: 338-344Crossref PubMed Scopus (117) Google Scholar). The findings by Suh et al., 2007Suh H. Consiglio A. Ray J. Sawai T. D'Amour K.A. Gage F.H. Cell Stem Cell. 2007; 1 (this issue): 515-528Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar suggest that the composition of adult neurogenic compartments can include more than one type of NSC. However, several questions remain unanswered. For example, does the subpendymal compartment contribute stem and progenitor cells to the SGZ in adulthood? What are the signals present within the SGZ microenvironment that would preserve the coexistence of NSCs with distinct proliferative behaviors? How does physical activity mobilize the relatively quiescent NSC subtype? Finally, although SOX2 expression within the SGZ appears to specifically mark NSCs, it does not independently distinguish between the two NSC subpopulations (or states), nor does it indicate that all NSCs express SOX2. Thus, what is the role of SOX2 in maintaining NSC identity in vivo at the transcriptional level? Regardless of the answers to these questions, Suh and colleagues have provided a new framework for improving our understanding of the complex, dynamic cellular composition of stem cell niches in the brain. In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Capacities of Sox2+ Neural Stem Cells in the Adult HippocampusSuh et al.Cell Stem CellNovember 15, 2007In BriefTo characterize the properties of adult neural stem cells (NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone (SGZ) express markers specific for progenitors, but they represent two morphologically distinct populations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate-tracing studies showed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing their multipotency at the population as well as at a single-cell level. Full-Text PDF Open Archive" @default.
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• W2038231738 title "Kinship and Descent: Redefining the Stem Cell Compartment in the Adult Hippocampus" @default.
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