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WIREs Dev Biol
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A mosaic world: puzzles revealed by adult neural stem cell heterogeneity

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Neural stem cells (NSCs) reside in specialized niches in the adult mammalian brain. The ventricular–subventricular zone (V‐SVZ), adjacent to the lateral ventricles, gives rise to olfactory bulb (OB) neurons, and some astrocytes and oligodendrocytes throughout life. In vitro assays have been widely used to retrospectively identify NSCs. However, cells that behave as stem cells in vitro do not reflect the identity, diversity, and behavior of NSCs in vivo. Novel tools including fluorescence activated cell sorting, lineage‐tracing, and clonal analysis have uncovered multiple layers of adult V‐SVZ NSC heterogeneity, including proliferation state and regional identity. In light of these findings, we reexamine the concept of adult NSCs, considering heterogeneity as a key parameter for analyzing their dynamics in vivo. V‐SVZ NSCs form a mosaic of quiescent (qNSCs) and activated cells (aNSCs) that reside in regionally distinct microdomains, reflecting their regional embryonic origins, and give rise to specific subtypes of OB interneurons. Prospective purification and transcriptome analysis of qNSCs and aNSCs has illuminated their molecular and functional properties. qNSCs are slowly dividing, have slow kinetics of neurogenesis in vivo, can be recruited to regenerate the V‐SVZ, and only rarely give rise to in vitro colonies. aNSCs are highly proliferative, undergo rapid clonal expansion of the neurogenic lineage in vivo, and readily form in vitro colonies. Key open questions remain about stem cell dynamics in vivo and the lineage relationship between qNSCs and aNSCs under homeostasis and regeneration, as well as context‐dependent plasticity of regionally distinct adult NSCs under different external stimuli. WIREs Dev Biol 2016, 5:640–658. doi: 10.1002/wdev.248 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Methods and Principles Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Aging
Architecture of the V‐SVZ niche. (a) Schema of the whole mouse brain showing the LVs (blue). The V‐SVZ lies adjacent to the walls of the LV, and generates neurons that migrate along the RMS to the OB. (b) Schema of coronal section at level of the plane shown in (a) showing the V‐SVZ (red) located between the lateral ventricles (light blue) and the striatum (Str). (c) Schema showing V‐SVZ cell types (modified from Ref ). aNSC, activated neural stem cell; BV, blood vessel; CSF, cerebrospinal fluid; E, ependymal cells; LV, lateral ventricle; Nb, neuroblasts; OB, olfactory bulb; pericytes (yellow); qNSC, quiescent neural stem cell; RMS, rostral migratory stream; V‐SVZ, ventricular–subventricular zone; TAC, transit amplifying cells.
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Aging‐related changes in V‐SVZ NSCs. NSC number decreases with aging due to a balance between intrinsic and extrinsic signals. Few studies have examined the effect of aging on qNSCs and aNSCs. Two nonexclusive models may explain the age‐related depletion of stem cells. (1) Model 1 suggests that NSC dynamics are altered with aging. This can be due to multiple factors including changes in NSC recruitment and/or division rate. (2) Model 2 proposes a progressive shift of adult NSCs toward deep quiescence. Whether NSC subpopulations (colored shapes) are depleted unevenly with aging, and whether neuronal and glial differentiation is altered, is unknown (question marks).
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Adult NSC plasticity in response to injury. (a) Under normal conditions, regionally distinct NSC subpopulations give rise to specific OB neurons (blue arrow). Gliogenic activity is also detected in the adult V‐SVZ: generation of oligodendrocytes in the corpus callosum (green), and astrocytes in the RMS/corpus callosum (red). (b) Multiple responses of V‐SVZ cells to stroke or ischemia. Neuroblasts are redirected to injury site (orange arrows); NSC migration to injury site and differentiation into reactive astrocytes (RA) (red arrows); migration of NSC‐derived astrocytes to injury site (blue arrows); and oligodendrocyte production at injury site (green arrows). The site of injury can be striatum, cortex or corpus callosum. (c) Response of V‐SVZ cells to demyelination. Adult NSCs predominantly give rise to oligodendrocytes in the corpus callosum. (d) qNSC response to injury. After irradiation, aNSCs (green circles) are depleted, resulting in recruitment of dormant qNSCs (purple circles) to a primed qNSC state and eventually to an aNSC state. qNSCs are also recruited via a primed qNSC state after ischemia.
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V‐SVZ niche components affecting adult NSC behavior. Diverse extrinsic sources of signals regulate NSC behavior in the V‐SVZ niche (light orange), including the lateral ventricle choroid plexus (LVCP), which produces cerebrospinal fluid (CSF), blood vessels (BV), systemic signals, cell–cell interactions, microglia, neuronal innervation, and extracellular matrix (ECM). qNSCs are dark blue, aNSCs light blue, TACs green, and Nb red.
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Regional identity of adult NSCs. (a) Left shows schema of coronal section of the embryonic brain highlighting germinal layers that have been fate mapped based on transcription factor expression to different domains in the adult V‐SVZ (right). Color code depicts the correspondence between embryonic and adult neurogenic zones. LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; Sp, septum. (b) Schema shows transcription factor microdomains in a three‐dimensional representation of the lateral ventricle walls. Lower ventricle shows the expression pattern of transcription factors along the lateral wall, and the upper ventricle shows the expression pattern of transcription factors along the medial wall. (c) DAPI image of coronal section of the olfactory bulb showing different subtypes of olfactory bulb interneurons derived from regionally distinct stem cells. The color code of the interneurons reflects the color code of transcription factor domains in the V‐SVZ walls in panel (b). Interneurons integrate into the superficial and deep granule cell layer (inner dashed line), as well as in the glomerular layer (outer dashed line). GL, glomerular layer; EPL, external plexiform layer; MCL, mitral cell layer; IPL, internal plexiform layer; GCL, granule cell layer.
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Molecular changes upon stem cell activation. Top: Schema of quiescent (left), primed‐quiescent (middle), and activated (right) adult V‐SVZ NSCs, located between the ependymal cell layer (E) lining the lateral ventricle (LV), and the vascular plexus (BV). Summary of transcriptome data of purified qNSCs and aNSCs at the population and single cell level. EGFR, epidermal growth factor receptor; GPCR, G‐protein coupled receptor; NSC, neural stem cell.
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Prospective purification of adult NSCs. (a) Combination of markers used for FACS purification of adult V‐SVZ qNSCs and aNSCs (colored circles). The degree of overlap between the isolated subpopulations is still unclear (question marks). Table shows functional properties of qNSCs and aNSCs. Whether a primitive population (light green circle on the left) lies upstream of GFAP+/GLAST+ qNSCs or is a subpopulation of qNSCs is still unclear. (b) Schema of ependymal cell (grey) pinwheel and CD133 (magenta) expression in ependymal cell cilia, and on the primary cilium of qNSCs and over the apical surface of aNSCs (GFAP+ and/or GLAST+ cells, blue cells). (c) CD133+ cells comprise both ependymal cells (hatched brown) and GFAP+ and/or GLAST+ adult qNSCs and aNSCs (intersection between brown, green and blue circles). Among CD133+ NSCs, q1, q2, a1, and a2 subpopulations have been described. aNSCs, activated NSCs; FACS, fluorescence activated cell sorting; GFAP, glial fibrillary acidic protein; GLAST, glutamate aspartate transporter; NSC, neural stem cell; qNSCs, quiescent NSCs; V‐SVZ, ventricular–subventricular zone.
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