A Specialized Vascular Niche for Adult Neural Stem Cells (original) (raw)
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Direct cell–cell contact with the vascular niche maintains quiescent neural stem cells
Nature Cell Biology, 2014
The vasculature is a prominent component of the subventricular zone neural stem cell niche. Although quiescent neural stem cells physically contact blood vessels at specialised endfeet, the significance of this interaction is not understood. In contrast, it is well established that vasculaturesecreted soluble factors promote lineage progression of committed progenitors. Here we specifically investigated the role of cell-cell contact-dependent signalling in the vascular niche. Unexpectedly, we find that direct cell-cell interactions with endothelial cells enforces quiescence and promotes stem cell identity. Mechanistically, endothelial ephrinB2 and Jagged1 mediate these effects by suppressing cell-cycle entry downstream of mitogens and inducing stemness genes to jointly inhibit differentiation. In vivo, endothelial-specific ablation of either of the genes which encode these proteins, Efnb2 and Jag1 respectively, aberrantly activates quiescent stem cells, resulting in depletion. Thus, we identify the vasculature as a critical niche compartment for stem cell maintenance, furthering our understanding of how anchorage to the niche maintains stem cells within a pro-differentiative microenvironment. Adult stem cells reside in specialized microenvironments, or niches, that maintain them as quiescent, undifferentiated cells to sustain lifelong regeneration 1-3. However, the molecular nature of the signals involved in stem cell maintenance or the cell types from which they originate within the niche remain largely unknown. The subventricular zone (SVZ) is one of the two germinal niches of the adult mammalian brain, where new neurons are continuously produced throughout life. Neurogenesis is initiated from quiescent type-B stem cells that Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015
Adult neural stem cells reside in specialized niches. In the ventricular-subventricular zone (V-SVZ), quiescent neural stem cells (qNSCs) become activated (aNSCs), and generate transit amplifying cells (TACs), which give rise to neuroblasts that migrate to the olfactory bulb. The vasculature is an important component of the adult neural stem cell niche, but whether vascular cells in neurogenic areas are intrinsically different from those elsewhere in the brain is unknown. Moreover, the contribution of pericytes to the neural stem cell niche has not been defined. Here, we describe a rapid FACS purification strategy to simultaneously isolate primary endothelial cells and pericytes from brain microregions of nontransgenic mice using CD31 and CD13 as surface markers. We compared the effect of purified vascular cells from a neurogenic (V-SVZ) and non-neurogenic brain region (cortex) on the V-SVZ stem cell lineage in vitro. Endothelial and pericyte diffusible signals from both regions dif...
The vascular niche in adult neurogenesis
Mechanisms of Development, 2015
Blood vessels (BVs) not only serve as conduits for oxygen and nutrients but may also fulfill perfusionindependent functions. A growing body of data suggests that blood vessels are an integral component of stem cell niches, including stem cell niches in the adult brain. This review summarizes in vivo studies supporting the contention that blood vessels may indeed control function of neuronal stem cells (NSCs) residing in the two major neurogenic niches of the adult brain, namely the sub-ventricular zone and the hippocampus. The review discusses different modes of BV-NSC communication and possible mechanisms by which BV may modulate NSC behavior and responses to external stimuli.
Cell Stem Cell, 2008
There is an emerging understanding of the importance of the vascular system within stem cell niches. Here, we examine whether neural stem cells (NSCs) in the adult subventricular zone (SVZ) lie close to blood vessels, using three-dimensional whole mounts, confocal microscopy, and automated computer-based image quantification. We found that the SVZ contains a rich plexus of blood vessels that snake along and within neuroblast chains. Cells expressing stem cell markers, including GFAP, and proliferation markers are closely apposed to the laminin-containing extracellular matrix (ECM) surrounding vascular endothelial cells. Apical GFAP+ cells are admixed within the ependymal layer and some span between the ventricle and blood vessels, occupying a specialized microenvironment. Adult SVZ progenitor cells express the laminin receptor a6b1 integrin, and blocking this inhibits their adhesion to endothelial cells, altering their position and proliferation in vivo, indicating that it plays a functional role in binding SVZ stem cells within the vascular niche.
Neurobiology of Disease, 2015
Previous studies have established the subventricular (SVZ) and subgranular (SGZ) zones as sites of neurogenesis in the adult forebrain . Work from our laboratory further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches . In the quiescent rat brain, NSC proliferation remains low in all of these sites. Therefore, we recently examined whether ischemic stroke injury (MCAO) or sustained intraventricular infusion of the mitogen bFGF could trigger an up-regulation in NSC proliferation, inducing neurogenesis and gliogenesis. Our data show that both stroke and bFGF induce a dramatic and long-lasting (14 day) rise in the proliferation (BrdU +) of nestin + Sox2 + GFAP + NSCs capable of differentiating into Olig2 + glial progenitors, GFAP + nestin-astrocyte progenitors and Dcx + neurons in the SVZ and CVOs. Moreover, because of the upsurge in NSC number, it was possible to detect for the first time several novel stem cell niches along the third (3V) and fourth (4V) ventricles. Importantly, a common feature of all brain niches was a rich vasculature with a bloodbrain-barrier (BBB) that was highly permeable to systemically injected sodium fluorescein. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites along the entire ventricular system, consistent with the potential for widespread neurogenesis and gliogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem-cell mediated brain repair.
Vascular niche for adult hippocampal neurogenesis
The Journal of Comparative Neurology, 2000
The thin lamina between the hippocampal hilus and granule cell layer, or subgranule zone (SGZ), is an area of active proliferation within the adult hippocampus known to generate new neurons throughout adult life. Although the neuronal fate of many dividing cells is well documented, little information is available about the phenotypes of cells in S-phase or how the dividing cells might interact with neighboring cells in the process of neurogenesis. Here, we make the unexpected observation that dividing cells are found in dense clusters associated with the vasculature and roughly 37% of all dividing cells are immunoreactive for endothelial markers. Most of the newborn endothelial cells disappear over several weeks, suggesting that neurogenesis is intimately associated with a process of active vascular recruitment and subsequent remodeling. The present data provide the first evidence that adult neurogenesis occurs within an angiogenic niche. This environment may provide a novel interface where mesenchyme-derived cells and circulating factors influence plasticity in the adult central nervous system.
Perivascular instruction of cell genesis and fate in the adult brain
Nature Neuroscience, 2011
The perivascular niche for neurogenesis was first reported as the co-association of newly generated neurons and their progenitors with both dividing and mitotically quiescent endothelial cells in restricted regions of the brain in adult birds and mammals alike. This review attempts to summarize our present understanding of the interaction of blood vessels with neural stem and progenitor cells, addressing both glial and neuronal progenitor cell interactions in the perivascular niche. We review the molecular interactions that are most critical to the endothelial control of stem and progenitor cell mobilization and differentiation. The focus throughout will be on defining those perivascular ligand-receptor interactions shared among these systems, as well as those that clearly differ as a function of cell type and setting, by which specificity may be achieved in the development of targeted therapeutics. Neural stem cells (NSCs) and more restricted neuronal and glial progenitor cells are dispersed widely throughout the adult vertebrate brain 1-3. Long after fetal development, multipotent NSCs continue to reside in the forebrain ventricles of experimental animals and humans alike 4,5 , whereas committed neuronal progenitor cells also remain in both the subependyma of the lateral ventricles 6-9 and the subgranular zone of the hippocampal dentate gyrus 10,11. In adult mammals, active neurogenesis persists in each of these regions, an extensive subject that has recently been reviewed elsewhere 12. In addition, a larger pool of glial progenitor cells pervades adult tissue parenchyma (reviewed in ref. 13). All of these progenitor populations persist in adult humans and, as such, all are potential therapeutic targets (reviewed in ref. 14). As stem cell progeny depart their localized niches of stem cell maintenance, they commit to more restricted lineages, at which point they are still mitotic, but subject to senescence 15. Accordingly, lineage-restricted neuronal progenitor cells of the forebrain subependyma and hippocampus serve as transit-amplifying cells 16,17 , as do glial progenitor cells of the white matter, which are similarly able to divide and yield phenotypically restricted daughters, and yet are incapable of sustained self-renewal 18. Many recent studies have investigated those features that both define and distinguish the stem cell microenvironment from that of transitamplifying progenitors (reviewed in ref. 19). These studies have revealed that, in both the mammalian ventricular wall 20,21 and hippocampus 22 , as well as in the neurogenic regions of the avian brain 23 , the local microvascular bed is important for providing a permissive environment for NSC expansion, neuronal differentiation and parenchymal migration. This
Brain Research, 2014
Neurovascular niche Vascular endothelial growth factor a b s t r a c t Interactions between neural progenitor cells (NPC) and endothelial cells (EC) from adult vascular beds have been well explored previously. However, the factors and signaling mechanisms that regulate neurogenesis and angiogenesis are most prevalent during embryonic development. This study aimed to determine whether embryonic brain endothelial cells from the periventricular region (PVEC) present an advantage over adult brain EC in supporting NPC growth and differentiation. PVEC were isolated from E15 mouse brains, processed, and sorted with immunomagnetic beads using antibodies against CD31/ PECAM. On immunofluorescence (IF) staining, nearly all cells were positive for EC markers CD31 and CD144/VE-Cadherin. In proliferation studies, NPC proliferation was highest in transwell co-culture with PVEC, approximately 2.3 fold increase compared to baseline versus 1.4 fold increase when co-cultured with adult brain endothelial cells (ABEC). (A.J. Thomas). b r a i n r e s e a r c h 1 5 6 5 ( 2 0 1 4 ) 8 -1 7
Vascular regulation of adult neurogenesis under physiological and pathological conditions
Frontiers in Neuroscience, 2014
Neural stem cells in the mammalian adult brain continuously produce new neurons throughout life. Accumulating evidence in rodents suggests that various aspects of adult neurogenesis, including the genesis, migration, and maturation of new neurons, are regulated by factors derived from blood vessels and their microenvironment. Brain injury enhances both neurogenesis and angiogenesis, thereby promoting the cooperative regeneration of neurons and blood vessels. In this paper, we briefly review the mechanisms for the vascular regulation of adult neurogenesis in the ventricular-subventricular zone under physiological and pathological conditions, and discuss their clinical potential for brain regeneration strategies.