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A Vascular Perspective on Neurogenesis

Written By

Joshua S. Goldberg and Karen K. Hirschi

Published: 24 April 2013

DOI: 10.5772/54980

From the Edited Volume

Neural Stem Cells - New Perspectives

Edited by Luca Bonfanti

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1. Introduction

The vasculature has been identified as a prominent feature across several stem cell niches, suggesting a crucial role in their regulation and maintenance. While a critical component of every organ and tissue, it has adopted specific features for specialized microenvironments. Most notably, the subventricular (SVZ) and subgranular (SGZ) zones of the adult brain harbor unique vascular plexi that are finely tuned to support neural stem cell (NSC) function and behavior. Whether it is through direct contact with, and paracrine signaling from, endothelial and mural cells that comprise blood vessels, or systemically via distribution of soluble factors from the circulation, the vasculature serves as a multifaceted stem cell niche regulator. As emerging evidence continues to emphasize the importance of vascular and nervous system interdependency, it is clear that the vascular compartment in the neural stem cell niche is uniquely poised to coordinate responses of both systems to ensure proper maintenance and regeneration, as needed.


2. Vascular composition and function in the brain

2.1. Brain vascular endothelium

The vasculature is a critical component of every organ and tissue, and has the remarkable ability to integrate systemic signals and directly regulate the local microenvironment. In general, the vasculature provides nutrients and protection; however, it has adopted specialized features for specialized microenvironments. Accordingly, not only does the composition of blood vessels vary (e.g. smooth muscle cell and pericyte coverage, perivascular cell recruitment, extracellular matrix (ECM) deposition), but heterogeneity among the endothelium itself is recognized. Indeed, this endothelial cell (EC) heterogeneity may be at the heart of their vast regulatory potential, allowing control of multiple processes. These include, but are not limited to, angiogenesis, microvascular permeability, vessel wall tone, coagulation and anticoagulation, blood cell generation and trafficking, inflammation, and microenvironment regulation [1-3]. From a functional standpoint, the endothelium displays an incredible division of labor, where a spectrum of responses, both to internal and external stimuli, is carried out. Thus, heterogeneity among the vascular endothelium is a core property bestowing vast regulatory potential [4].

Within the brain, capillaries are tightly integrated within the neural parenchyma. As arterioles traverse deeper into the brain, they become progressively smaller and lose portions of their smooth muscle layer, and are thus termed cerebral capillaries [5]. These capillaries are tubes of EC that are variably surrounded by pericytes or pericyte processes, astrocytes, neurons, and ECM. This minimal composition of capillaries allows for a unique interface that facilitates communication with the underlying tissue environment. Distribution of cerebral capillaries within the brain is relatively heterogeneous, due to regional differences in blood flow and metabolic demand. Owing to their thin walls and slow rate of blood flow, capillaries are engineered to minimize diffusion path length and optimize diffusion time [2]. Surprisingly, the average luminal diameter is ~4.8 µm [6], a length that is somewhat smaller than the diameter of an erythrocyte, requiring red blood cells to deform slightly as they progress through these vessels.

The brain endothelium is characterized by unique features that allow it to selectively control permeability between blood and the central nervous system, which manifests as the blood-brain-barrier (BBB). Specifically, this endothelium is discontinuous and nonfenestrated, with few caveolae at the luminal surface and large numbers of mitochondria [7]. The barrier function is mediated by both a physical barrier, owing to high expression of tight interendothelial junctions, and a highly selective transport system. Interestingly, the basal lamina in capillary beds is common with that of perivascular astrocytic endfeet and pericytes, allowing direct contact of neural cells with the underlying endothelium [8]. These capillary EC are ~0.1 µm thick, giving them a cell volume of only ~20µL/cm3, cumulatively amounting to just 0.2% of the volume of the entire brain [9]. As the demand for energy must be matched by nutrient supply, the remarkable thinness and surface area of these EC allows for quick, selective, and efficient transport across endothelial membranes.


3. Development and vascularization of the brain

3.1. Embryonic brain development

The initial steps of central nervous system (CNS) development occur prior to gastrulation, beginning with neural plate induction from ectoderm [10]. The neural plate is then patterned along its anterioposterior (AP) and dorsoventral (DV) axes in a dose-dependent fashion, where gradients of secreted morphogens specify distinct neural fates by inducing expression of region-specific transcription factors. It has been reported that fibroblast growth factor (FGF), retinioic acid, and secreted Wnt family members determine AP polarity, while bone morphogenetic proteins (BMPs) and members of the Hedgehog family control mediolateral polarity [11-18]. As the neural tube fuses from the neural plate, the neuroepithelium begins to undergo a complex series of morphological transformations, and begins expressing proteins such as vimentin and nestin, thus marking the first appearance of radial glia in the cerebral cortex [19]. The appearance of projection neurons, originating from the neuroepithelium between E8.5 and E10, is followed closely by the onset of neurogenesis at E11 [20].

In the early stages of embryonic neurogenesis (E11-E13), the first mitotic cortical neurons leave the VZ to form the preplate via interkinetic nuclear migration, independent of radial fibers, creating an intermediate zone (IZ) where postmitotic neurons accumulate to commence differentiation [21]. Subsequently generated neurons continue to leave the VZ and enter the preplate to form the CP (E13-18), further subdividing this region into the subplate and marginal zone (MZ), where the latter becomes lamina I, the most superficial layer of the brain [22]. At this same time, SVZ progenitors generated in the VZ divide and expand the progenitor pool. Excluding layer I, subsequent development is said to occur in an “inside-out” manner, where earlier-born neurons reside in the deeper layers (V, VI), and later-born neurons occupy the more superficial layers (II,III) [23].

Between E11 and E18, neurons proceed radially from the ventricular zone (VZ) to the CP, while interneurons originating from the ganglionic eminence migrate tangentially, traveling perpendicular to radial fibers and parallel to the pial surface [24]. As these neurons reach their final destination, migration ceases, detachment from radial glia occurs, and differentiation begins. Cell lineage studies have revealed that proliferative progenitors of the neural epithelium are for the most part multipotent up until their final mitosis [25-30]. However, committed progenitors appear to be an exception, as their existence in secondary proliferative zones, such as the SVZ and other regions in the adult, have been documented to give rise to various neuronal subtypes, astrocytes, and glia [31, 32].

3.2. Vascularization of the brain

The brain, in general, has a specialized vasculature relative to other organs, and there are specialized microenvironments within the brain that exhibit distinct characteristics and functions. For example, it has been proposed that a unique vascular plexus exists in neurogenic regions of the brain, both during embryonic and adult neurogenesis [33-35], where EC-NSC interactions aid in stem cell maintenance while promoting cell division and NSC expansion [36, 37]. How then, does the vasculature become specialized to fulfill such distinct roles, even within the same tissue?

During early stages of embryonic brain development, the perivascular neural plexus (PVNP) forms around the neural tube at E8.5-E10, from anterior to posterior, yet does not invade the neural tissue until later in development [38]. During E10-E11, the periventricular vascular network advances into the dorsal telencephalon, and by E11 forms a lattice shaped plexus. However, a distinct vascular plexus of periventricular vessels appears in the ventral telencephalon at E9, and by E13 EC invasion into the ventricular zone (VZ) and subventricular zone (SVZ) has generated radially oriented capillaries that extend towards the cortical plate (CP), eventually joining the pial vasculature [39, 40].

Recently, the identification of distinct vascular origins within the developing brain [41] suggests that specialized features of vascular beds of adult germinal regions may begin during embryonic development and persist into adolescence. Previously, the long-standing model of CNS angiogenesis suggested that pial vessels, originating from the perineural plexus surrounding the neural tube, passively sprout into the brain parenchyma and extend radial branches toward the ventricles, where the neurogenic VZ and SVZ are established. Upon arrival to the periventricular area, these pial vessels were thought to form new branches, reverse direction to grow towards the pial surface, and ultimately branch into plexuses [42-44]. However, recent studies suggest that pial and periventricular vessels not only have distinct origins, but develop along independent schedules. In fact, periventricular vessels in the ventral telencephalon are thought to originate from a basal vessel, most likely arising from pharangeal arch arteries [42, 45], situated on the floor of the telencephalic vesicle within the basal ganglia primoridum. As early as E9, pial vessels are observed to encircle the telencephalon, while a spatially distinct population of periventricular vessels is restricted to the ventral telencephalon. From E9-E10, the basal vessel matures to produce periventricular branches in a ventral-to-dorsal and lateral-medial direction, eventually giving rise to a vascular lattice in the dorsal telencephalon. As narrow branches from the periventricular and pial networks fuse, the first arterial-venous communication is thought to occur, as early reports suggest venous sinuses and arterial networks develop from pial and periventricular vessels, respectively [41, 45]. At E15, the first tangential vessels to the pial surface emerge in the intermediate zone, and by E16, these vessels appear in the presumptive rostral migratory stream (RMS). By E18, extensive vascular remodeling has taken place, and the ventricular plexus loses much of its definition. However, upon reaching postnatal ages and adulthood, blood vessels begin to align themselves longitudinally and parallel to each other in the direction of the RMS, presenting a more homogeneous structure [35, 40].

Interestingly, the periventricular vascular network is present in the telencephalon prior to the formation of neuronal networks and before the appearance of radial units and striosome-matrix compartments in the dorsal and ventral telencephalon, respectively. Thus, the periventricular network is temporally and spatially poised to influence neural maturation, as well as guide tangential migration in the developing brain [41]. A similar vascular niche for NSC has been reported to exist in the adult SVZ and SGZ, and may have been established early during embryonic brain development. This suggests that the vasculature may be critical in promoting and regulating neural development.

3.3. Establishment of neurogenic regions of the brain

During brain development, three different NSPC types make their appearance in a tightly coordinated spatiotemporal manner, seeding the brain with committed progenitors that differentiate into the various cell types of the mature brain. The first of these to appear are pseudostratified epithelial cells termed radial glia, regarded as the bona fide NSC in the embryonic VZ [46, 47]. Morphological studies have identified two processes emanating from their cell bodies, suggesting an inherent bipolar nature. A short and thick apical process directed towards the ventricle is thought to anchor radial glia, while a longer basal radial fiber projects towards the basement membrane of the pia mater, acting as a scaffold for prospective neuronal migration [21, 48]. These radial fibers are often observed to contact blood vessels and exhibit multiple branched endfeet at the pial surface [49]. Interestingly, their apical regions are typically folded and contain a single cilium [50, 51], reminiscent of the proposed location, structural morphology, and vascular contacts of adult NSC in the SVZ.

During the early stages of cortical development, the cerebral cortex is composed almost exclusively of proliferative radial glia dividing at the ventricular surface in the VZ [52]. As proliferating radial glia progress through the cell cycle, they undergo interkinetic nuclear migration, where the nucleus migrates away from the ventricle during G1 phase, and enters S phase at the top of the VZ. Upon return through the VZ to the ventricular surface, they proceed through G2 phase and M-phase, respectively [19, 52-54]. A switch from symmetric self-renewing to asymmetric neurogenic divisions occurs as development proceeds, leading to pairs of daughter cells with distinct progenitor or early neuronal fates; symmetric divisions have also occasionally been observed to produce early neurons or intermediate progenitor cells (IPC) [19, 23, 49]. However, during peak neurogenesis, radial glia give rise to one radial glial cell, and either one post-mitotic neuron or a neuronally committed IPC [49, 55]. Similarly in adult neurogenesis, adult NSC asymmetrically divide to generate transit-amplifying cells that produce committed progenitors. In both cases, regulation of the symmetry of cell division is critical, and ultimately controls cerebral cortical size during brain development [52].

At the onset of neurogenesis, radial glia progeny migrate away from the ventricle and begin to establish the first layers of the developing brain, separate from the VZ. IPC establish the SVZ as a distinct proliferative region, while young cortical neurons migrate to a superficial position to establish the cortical plate [48]. These migrating cortical neurons are intimately associated with the long pial fiber of radial glia, utilizing it to traverse relatively long distances to the overlying cortex in a process termed radial migration. Once telophase is complete and radial glia have entered M-phase, the apical plasma membrane becomes unequally segregated into the two daughter cells. Interestingly, the apical daughter inherits a larger portion of the membrane while the basal daughter receives a smaller proportion in addition to the radial fiber, indicating the latter assumes the stem cell radial glia fate [46, 47, 49, 56]. However, this is not absolute, as instances of basal daughters becoming post-mitotic and apical daughters remaining proliferative have been reported. Instead, it has been suggested that fate decisions involving asymmetric division may also depend on developmental stage [47, 48]. Thus, the function of radial glia is two-fold, wherein they generate and guide migration of their own daughter cells [52, 57].

After the VZ reaches its maximal size during midstage cortical neurogenesis, the VZ begins to shrink while the SVZ begins to expand [57]. Derived from radial glia, IPC are the first cell types to initially seed the SVZ [48]. While some observations describe the distribution of IPC throughout the upper VZ and lower intermediate zones [49, 58], they are predominantly concentrated in the SVZ, where they almost exclusively divide symmetrically to generate postmitotic daughter neurons [59-62]. In contrast to radial glia, IPC are multipolar, extending and retracting multiple processes [19, 49]. Additionally, they do not appear to sustain contact with either the ventricular or pial surfaces, and are in fact defined by their lack of prominent apical or basal processes and a basal location relative to the apical surface [52]. While their contact with neighboring blood vessels has not been confirmed, their appearance in the cortex seems to follow that of blood vessel invasion in the cortical wall [19]. Furthermore, behavioral differences between radial glia and IPC have been noted. IP cells progress through the cell cycle away from the ventricle, and do not undergo interkinetic nuclear migration, thus, allowing differentiation from radial glia based on spatial location during mitosis [19, 63].

At later stages of cortical development, the SVZ progenitor pool continues to expand via IPC symmetric divisions. Further aiding in expansion, progenitors from the ventral telencephalon may even migrate dorsally to contribute to the SVZ progenitor pool [19]. Upon completion of cortical neurogenesis, radial glia transition into astrocytes and exit the VZ, leaving a single layer of ependymal cells lining the ventricle [57]. Consequently, proliferative IPC become the predominant component of the cortical progenitor pool, and eventually comprise the majority of mitotic progenitors as embryonic neurogenesis nears completion. Interestingly, while only a single layer of VZ-derived ependymal cells remains postnatally, IPC are present in large numbers in the postnatal SVZ, and persist into adulthood [19]. Aside from generating cortical neurons, postnatal and adult progenitors have been demonstrated to generate neurons destined for the olfactory bulb [49, 58, 64], and possibly all excitatory neurons of the upper cortical layers [58]. Thus, IPC in the SVZ play a vital role in cortical neurogenesis during embryonic development as well as in the adult.

Interestingly, a novel progenitor type termed the outer SVZ (OSVZ) progenitor has recently been identified and appears to exist in all mammals, albeit to varying extents [52]. These progenitors have a modified radial morphology, but are exclusively localized to the SVZ. OSVZ cells are enriched in mammals with larger cerebral cortices, and their appearance during mid-gestation seems to coincide with the onset of neurogenesis [52, 65-69]. OSVZ progenitors are peculiar in that they possess characteristics reminiscent of both radial glia and IPC. They display radial morphology and express radial glial markers paired box protein-6 (Pax6), phospho-vimentin, glial fibrillary acidic protein (GFAP), and brain lipid-binding protein (BLBP), and also display random cleavage planes, where both proliferative self-renewing symmetrical divisions and asymmetric divisions producing OSVZ daughter and progenitor have been reported. However, an apical process is absent in these cells while their basal process is retained throughout mitosis [65-67].

3.4. Vascular cues during embryonic neurogenesis

It has been suggested that the developing cortical vasculature within the SVZ promotes IPC expansion during neurogenesis by providing a suitable microenvironment for IPC accumulation and division [39]. It is noteworthy that brain EC share similar molecular profiles with their neighboring NSC. For example, ventral and dorsal EC, as well as NSC, express Dlx1/5 and Nkx2.1, and Pax6, respectively, while pial EC are negative for all three [41]. This strongly suggests that mechanisms of patterning during early angiogenesis and neurogenesis in the brain are shared.

A strong association between NSC and blood vessels exists during embryonic and adult neurogenesis, especially in regard to cell cycle regulation [33-35]. The filopodia of endothelial tip cells extend towards the ventricular surface where radial glia divide, and even interact with pial fibers of radial glia in the hindbrain [39]. Additionally, dividing cells in the embryonic SVZ reside statistically closer to blood vessels than predicted by chance, and recent studies report a synchronization of SVZ cell division with the formation of ventricular vascular plexuses [40]. This vascular relationship is apparent in the emerging RMS as well, where dividing cells have been reported to associate with blood vessels at E16, E18, and P4 [35]. On the other hand, progenitor migration in the RMS does not seem to rely on the vasculature, as the vast majority of neuroblast neurites in P4 RMS have little or no association with blood vessels [35]. This is in contrast to radial migration outside the RMS, where postmitotic doublecortin (DCX) and glial fibrillary acidic protein (GFAP)-positive cells associate with blood vessels during migration into superficial cortical layers [40]. Interestingly, IPC have been suggested to maintain a stronger interaction with blood vessels, as T-brain gene-2 (Tbr2)-eGFP progenitors in M-phase reside closer to blood vessels when compared to total phosphohistone H3-positive progenitors [40]. Furthermore, these dividing IPC are often found at vessel branch points, which have previously been observed to be sites of glial tumor mitosis and subsequent migration [70].

Mounting evidence suggests that Tbr2 progenitors are temporally and spatially correlated with the appearance of cortical vasculature, and even follow and mimic the pattern of nascent blood vessels. Similarly, the positions of IPC during mitosis, migration and differentiation are all correlated with EC development in the SVZ. Even detection of Tbr2-positive cells correlates with the appearance of vascularization, as Tbr2 cell density is highest in the vascularized lateral regions as compared to the nearly avascular medial regions in the dorsal cortex of E12 embryos [39]. Moreover, ectopic overexpression of vascular endothelial growth factor (VEGF)-A causes IPC to follow a pattern of aberrant vascular growth. Interestingly, leading EC tip cells have been observed to associate with some Tbr2-positive IPC in M-phase, suggesting a functional interaction during division. These data collectively suggest the SVZ vasculature serves as a niche for mitotic IPC [39], and provides instructive and permissive cues for stem and progenitor cell expansion and tissue invasion [71].

3.5. Parallels between embryonic neurogenesis and adult neurogenesis

Similarities between embryonic and adult NSC at the cellular level and across their extracellular microenvironments have been reported, and selective labeling of radial glia has demonstrated a direct link between these cells, indicating that NSC are most likely contained within the neuroepithelial-radial glia-astrocyte lineage [72, 73]. Furthermore, reports indicate adult SVZ NSC retain specialized characteristics of radial glia. However, the molecular characteristics that confer progenitor potential onto astroglial cells and distinguish them from those with normal support function remain largely unknown [53].

From adult NSC, also referred to as Type B cells in the SVZ, an apical process at times intercalates between ependymal cells lining the lateral ventricular surface, potentially serving to both anchor and present NSC to circulating factors in the cerebrospinal fluid (CSF). Embryonic radial glia also share this apical process, and most likely contain a similar profile of specialized apical junctions at the site of this primary cilium [53]. Similarly, the longer basal process that radial glia extend towards the surface of the brain during embryonic development is also shared by adult NSC of the SVZ. In the adult SVZ, this basal process projects radially or tangentially, depending on location, eventually terminating in specialized endfeet on the surface of blood vessels [33, 74, 75]. These vascular contacts may be analogous to those of radial glia during development, as branch contacts with the overlying vasculature also occur [53]. This suggests that adult SVZ NSC share core properties with the embryonic radial glia from which they are derived from, allowing them to retain progenitor function throughout life.

These similarities are also observed in adult NSC of the SGZ in the hippocampal dentate gyrus. Early anatomical studies suggest that radial glia in the dentate neurepithelium transition to the different astrocyte populations of the dentate gyrus, including radial astrocytes [76, 77]. While experimental evidence linking radial glia to adult SGZ radial astrocytes is lacking [53], it is possible that this derivation occurs, and further studies will be needed to clarify this lineage relationship. However, the primary cilium of radial glia is present on SGZ progenitors and adult radial astrocytes, and is essential for progenitor proliferation and generation of postnatal radial astrocytes, thus establishing its requirement for neurogenesis. From a signaling standpoint, the primary cilium serves as an integration site for signaling via pathways such as Shh. Interestingly, this cilium seems to be specific to the radial astrocytic NSC pool in the hippocampus. Non-stem cell astrocytes are not affected by lack of primary cilium or Shh signaling, suggesting a unique requirement among these NSC [78, 79].

As in the adult SVZ [80], location seems to dictate specificity, where radial glia in the dorsal telencephalon generate only pyramidal excitatory neurons, while those located in the ventral telencephalon give rise to nonpyramidal inhibitory interneurons [81]. Studies from several mouse models demonstrate that neurons can migrate into the cortical plate (CP) radially or tangentially [82-84]. This type of migration is mirrored in the adult SVZ, where neuroblast progenitors migrate tangentially through the rostral migratory stream towards the olfactory bulb, destined to become inhibitory interneurons. Features of interkinetic nuclear migration are also shared by radial glia and adult NSC. While mitotic cells are found only adjacent to the lumen of the neural tube, nuclei of cells in S-phase are found in the outer half of neural epithelium [19, 54]. This correlation of cell cycle with spatial location occurs in the adult SVZ as well, where basally located blood vessels are proposed to exert growth control over proximal NSC by providing a proliferation-inducing microenvironment. This is in contrast to NSC located apically, either adjacent to or within the ependymal layer, which are immunoreactive for mitotic markers [33, 34, 75, 85].

These findings highlight basic properties that are common to embryonic radial glia and adult SVZ and SGZ NSC. Given the evidence, it is highly likely that a microenvironment similar to the one which supports embryonic neurogenesis persists throughout development and is maintained in the adult neural stem cell niche.


4. The adult NSC niche

4.1. Cellular architecture of the adult SGZ and SVZ

As previously mentioned, two prominent germinal regions of the adult brain have been identified to function as stem cell or neurogenic niches, allowing for continuous generation of new neurons. The SVZ represents the largest neurogenic stem cell region within the adult brain. It resides within a narrow region of the lateral ventricular wall, roughly four to five cells in diameter [86]. Progenitors generated from this region migrate through the RMS towards the olfactory bulb, where differentiation into at least five interneuron subtypes has been reported. In fact, it is estimated that 30,000–60,000 new neurons are generated in the rodent olfactory bulb per day [87, 88]. Differentiation into oligodendrocytes of the corpus callosal white matter also occurs, albeit to a lesser extent [89, 90]. A second neurogenic region, the SGZ, is located between the hilus and the granule cell layer of the dentate gyrus within the hippocampal formation. In contrast to SVZ progenitors, granule neurons born from this region migrate short distances to the granule cell layer, where differentiation commences [91]. Whether bona fide NSC exist in the adult mammalian hippocampus is currently under investigation, as in vivo lineage tracing assays suggest that separate progenitors responsible for neurogenesis and gliogenesis exist in the SGZ [92-94].

A group of distinct cell types in the adult SVZ help maintain this specialized niche microenvironment: putative NSC (type B cells), transit-amplifying cells (type C cells), neuroblasts (type A cells), ependymal cells, and specialized vascular endothelium [34, 95]. There is no definitive marker of NSC, and researchers rely on combinations of overlapping markers, as well as spatial location within the niche to identify NSC. Accordingly, NSC are usually identified by their apical location, superficial to the ependymal layer, and slow cell cycle time of ~ 28 days [96]; however, their expression of Sox 2 and 9, GFAP, and CD133/prominin-1 are not exclusive [33, 34, 74]. The presumptive lineage progression from stem cell to more differentiated progenitor is as follows: NSC generate transit amplifying cells that differentiate into migrating neuroblast progenitors.

Non-dividing ependymal cells are multiciliated, and form a single layer lining the ventricle surface, acting as a physical barrier separating the brain parenchyma from the cerebrospinal fluid (CSF) [97]. While ependymal cell cilia contribute to CSF flow, they have also been reported to affect the migration of young neurons by creating gradients of Slit chemorepellents that guide anterior neuroblast migration [98]. An en face view of the lateral ventricle wall reveals a planar organization, commonly referred to as “pinwheel organization”, where the apical process of NSC is surrounded by a mosaic of ependymal cells [33, 74, 99]. Through studies mapping numbers of ventricle-contacting NSC along the ventricular surface, “hot spots,” or areas of stem cell activation, have been revealed [100-102]. Currently a topic of debate is whether ependymal cells can function as multipotent NSC. Previous studies have demonstrated that CD133/prominin-1 positive ependymal cells are in fact multipotent, and during ischemia become active to generate neuroblasts and astrocytes [103, 104]. However, a more recent study using split-Cre technology demonstrated a subset of CD133/prominin-1 positive cells within the ependymal layer are immunoreactive for GFAP, suggesting that these double positive radial-like cells are NSC, not ependymal cells [98, 105].

Two astrocytic populations have been proposed to reside in the SVZ [100]. Type B NSC astrocytes reside underneath the ependymal layer, while non-stem cell astrocytes are more superficial and differ in morphology [33, 34, 74, 99]. NSC are closely associated with ependymal cells, and at times extend a short, apical, non-motile primary cilium that innervates between the ependyma to directly contact the CSF within the ventricle [33, 74, 99]. While NSC are relatively quiescent, transit-amplifying cells are highly proliferative, and remain localized to the SVZ [95, 100]. Neuroblasts, on the other hand, migrate through astrocytic tubes in the RMS to the olfactory bulb, where interneuron differentiation occurs [106, 107]. Interestingly, experiments using viral targeting and genetic lineage tracing in neonatal and adult mice have revealed that specific subtypes of interneurons in the olfactory bulb are derived from specific locations within dorsal, medial, and ventral portions of the adult SVZ [108-112]. Interestingly, while the vascular beds of the SVZ and SGZ both support adult neurogenesis, the SVZ vasculature is somewhat unique. Differences in permeability, stability, and perivascular cell coverage are thought to account for these differences. NSC and transit-amplifying cells both display an intimate relationship with SVZ blood vessels, as 3-dimensional niche modeling indicates closer proximity and increased vascular contact relative to other SVZ cells. Interestingly, these vascular associations are further exaggerated in niche regeneration models [33, 34]. Additionally, NSC extend a long basal process that terminates on blood vessels in the form of specialized endfeet, potentially serving to integrate vascular cues [33, 74, 99].

4.2. NSC-Vascular EC associations within the SVZ and SGZ

NSC are not randomly distributed throughout the brain; rather, they are concentrated around blood vessels, allowing constant access to circulating signaling molecules and nutrient metabolites [113, 114]. The SVZ and SGZ both present functional neurogenic environments, maintaining neural stem and progenitor cells (NSPC) in poised and undifferentiated states. Regulatory processes within the SVZ niche can be controlled via secreted neurotrophic and angiogenic factors, such as Wnt, Shh, and TGF-β [115]. For example, circulating complement factors have been shown to promote basal and ischemia-induced neurogenesis, and components of complement signaling are present on transit-amplifying cells and neural progenitors in vivo [116]. The vascular-derived factors, stromal cell derived factor (SDF)-1 and angiopoietin (Ang)-1, promote neuroblast proliferation and survival [117], and when expressed on EC, serve as “molecular migratory scaffolds” [118, 119] to damaged areas post stroke [120]. EC themselves have even been shown to regulate NSC self-renewal [37, 86, 101, 121]. Interaction with the vascular endothelium may in fact be a vital component of the niche, as radiation-induced disruption of endothelial cell–SGZ precursor cell interaction results in a loss of neurogenic potential, as is the case after NSC transplantation into an irradiated host. [122].

Within the SGZ, nestin-expressing radial astrocytes are localized to areas near blood vessels [91], and there exists an anatomical relationship between proliferating neural progenitors and EC in the hippocampus [101, 123, 124]. In contrast to the SVZ, where angiogenic sprouting and division of EC are absent [34], surges of EC division are said to be spatially and temporally related to clusters of neurogenesis in the SGZ [101]. In the hippocampus, angiogenesis and neurogenesis are coupled, as suggested by high levels of VEGF and VEGFR2 [101], and the shared responsiveness to similar growth factors, e.g., neurotrophins, neuropilins, semaphorins and ephrins [125-127]. In fact, similar bidirectional communication occurs within the higher vocal center (HVC) of the songbird brain, where increases in angiogenesis are said to be coupled to testosterone-induced upregulation of VEGF and VEGFR2 in neurons and astrocytes, respectively. The newly generated capillaries produce BDNF (brain-derived neurotrophic factor) that subsequently promotes the recruitment and migration of newly born neurons [121]. Similarly, exercise-induced angiogenesis in the hippocampus is met with increased expression of NGF (nerve growth factor) and BDNF [126], leading to robust increases in neurogenesis [128-130].

In contrast to other areas of the brain, where the BBB is strictly maintained by EC tight junctions, pericyte coverage, and astrocyte endfeet, a modified BBB has been proposed to exist in the SVZ. The lack of astrocyte endfeet and endothelial cell tight junctions, as revealed by aquaporin-4 and zonula occludens-1 immunostaining, respectively, demonstrate major structural differences in the SVZ vascular endothelium. Under homeostatic conditions, the majority of BrdU+ label-retaining NSC and transit amplifying cells reside significantly closer, and frequently make direct contact, to the vasculature; furthermore, after antimitotic cytosine-β-D-arabinofuranoside (Ara-C) treatment to ablate rapidly proliferating cells and induce NSC-mediated repopulation, these vascular associations are increased [33, 34]. At times, transit-amplifying cells can be seen contacting the vasculature at sites lacking astrocyte endfeet and pericyte coverage, suggesting that sites along the vessel are primed for intercellular communication. In fact, fluorescent tracer experiments have proposed that differences in the ultrastructural composition of SVZ blood vessels may be responsible for the detection of sodium fluorescein in the SVZ after perfusion into the blood; however, access to the SVZ from the cerebral spinal fluid cannot be dismissed as an entry point. Integrin-α6β1 partially mediates the adhesion between NSPC and blood vessels through the binding of laminins that are highly concentrated around SVZ blood vessels. In vitro and in vivo blocking experiments using an integrin-blocking antibody (GoH3) have demonstrated a crucial role for this interaction in the attachment, spreading, and proliferation of NSPC [33].

The vascular environment in the RMS has also been suggested to be somewhat specialized, where migrating neuroblasts en route to the olfactory bulb are found closely apposed to blood vessels. Interestingly, blood vessels in this region are parallel and aligned with the direction of the RMS, and the density of vessels is significantly higher when compared to equally cell-dense areas of the brain [131]. It has been reported that over 80% of RMS vessels are lined with migrating neuroblasts [132], and degradation of ECM through vascular EC secretion of matrix metalloproteinases (MMPs) opens a path for their migration [133]. This observation has prompted some to suggest that increased vessel density is a consequence of greater metabolic demand by migrating progenitors.


5. Vascular regulation of adult neurogenesis

5.1. EC regulation of NSPC

Through cytokines and secreted factors, direct contact in vivo, or within the confines of the coculture system, EC exert their influence over NSC to regulate fate specification, differentiation, quiescence and proliferation (Figure 1). Early experiments established a crude role for EC regulation of NSC, where increases in neurite outgrowth and maturation, and enhanced migration were observed in cocultures of SVZ explants with EC [134]. NSC are reported to respond to pro-angiogenic factors [135-137] that promote NSPC proliferation, neurogenesis, synaptogenesis, axonal growth, and neuroprotection [138]. Studies in tumor and stroke models have also uncovered neural regulatory roles of EC. EC can protect stem cells and tumor cells from radiation damage [139, 140], and in preclinical models where NSPC isolated from stroke boundary are cocultured with cerebral EC, significant increases in neural progenitor cell proliferation, neuronal differentiation, and capillary tube formation are observed [141]. Even cotransplantation of EC with NSPC increases survival and proliferation as compared to transplantation of neural precursors alone [142]. Similarly, coculture of adult NSC with EC results in self-renewal and symmetric neural cell division, leading to enhanced neurogenesis through an increase in nestin+ precursor number [37]. Interestingly, when stroke-activated rat brain EC are cocultured with SVZ cells, progenitor proliferation and neuron number are increased by 28% and 46%, respectively, when compared to coculture with normal EC. This suggests that activated EC are more potent in promoting neurogenesis, potentially through modulation of Sox2 and Hes6 levels in SVZ cells [143], although further investigation is required to identify the mechanisms involved.

Figure 1.

Regulatory effects on adult neural stem and progenitors

Mock treatment with serum-rich endothelial growth media induces NSC differentiation into neurons and astrocytes [31], indicating that EC-mediated regulation of NSPC self-renewal and differentiation may be mediated through the release of certain growth factors, including PEDF or VEGF [144, 145]. Cytokine expression profiles of human umbilical vein and cerebral microvascular EC reveal that a large number of chemokines, growth factors, adhesion molecules and ECM proteins are expressed by these cells [146]. Levels of these signaling molecules varied under stimulating and nonstimulating conditions as well as by EC type, highlighting the diverse signaling potential that exists even among endothelial subtypes. Studies of adult neurogenic niche regulation have identified a number of growth factors and secreted molecules, although the origin of some remains unknown (Figure 2).

Figure 2.

Putative vascular – derived regulators of the adult neural stem cell niche*

The vascular-derived molecules shown to locally regulate the adult NSC niche include leukemia inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF), VEGF, platelet-derived growth factor (PDGF), pigment epithelial-derived factor (PEDF), betacellulin (BTC), and laminins and integrins [33, 121, 147]. However, there are additional factors reported to influence NSPC behavior which may be derived from the NSC niche vasculature, although this has not yet been demonstrated, including fibroblast growth factor 2 (FGF-2), epidermal growth factor (EGF), interleukin-6 (IL-6), stem cell factor (SCF), insulin growth factor-1 (IGF-1), transforming growth factor-β (TGF-β), bone morphogenic proteins (BMP), SDF-1/CXCR4, collagen IV, Eph/ephrins, angiopoietin, nitric oxide (NO), erythropoietin and prolactins. We review advances made toward understanding the cellular and molecular role of these factors since last reviewed [148].

5.2. Endothelium-derived niche effectors

5.2.1. VEGFs

VEGF signaling is a complex signaling hierarchy involving several isoforms (e.g., VEF-A, -B, -C, -D) that result from alternative splicing of the VEGF gene. VEGFs are highly implicated in NSPC survival, proliferation, and neuroblast migration and maturation [149-154]. Along with the recent identification of VEGFR3/Flt4 expression in the adult SVZ, all corresponding receptors, including VEGFR1/Flt1 and VEGFR2/Flk1, are expressed within the NSPC pool [149, 154, 155]. While VEGFR1 negatively regulates adult olfactory neurogenesis and RMS migration by altering VEGF-A bioavailability, VEGFR2 and VEGFR3 both appear to positively regulate neurogenesis [133, 155]; in addition, VEGFR2 has also been reported to affect vascular proliferation [154]. This ability of VEGF family members to regulate both neurogenesis and angiogenesis may be important in clinical settings of intracerebral hemorrhage, where transplantation of human NSPC overexpressing VEGF have been shown to increase microvessel density and promote NSPC engraftment in sites of tissue damage [156, 157].

In VEGFR1 signaling-deficient (Flt-1 TK-/-) mice, the increased levels of VEGF-A and subsequent phospohorylation of VEGFR2 in NPSC are thought to account for the altered RMS migration, demonstrating a critical role for VEGF-A in this process [154]. Reported to be required for hippocampal neurogenesis in the adult rat [145], EC, ependymal cells and the choroid plexus secrete VEGF at neurogenic sites, which serves as a survival factor to stimulate NSPC self-renewal. Neurospheres, as well as reactive astrocytes, have been shown to express VEGF-A [158, 159], and infusion into the lateral ventricle after cerebral ischemia acts as a trophic survival factor for NSPC and increases neurogenesis, most likely through the VEGFR2/Flk-1 receptor [37, 150, 152]. Similarly, other studies suggest that in vitro VEGF stimulation increases the number of BrdU-labeled precursors, which is attenuated in the presence of SU1598, a Flk-1 receptor tyrosine kinase inhibitor, further supporting mediation through VEGFR2/Flk-1 [123]. Although VEGF-A is reported to have a direct role in signaling during development [101, 123, 150], evidence also supports an indirect role when it is secreted by ependymal cells, through the stimulated release of BDNF from EC [121, 152].

However, in experiments comparing the numbers of primary Ki67+ adult neural precursors in NestincreFlk1+/− and NestincreFlk−/− short-term cultures, it was found that VEGF-A signaling does not appear to affect the proliferation of these cells, and individual neurospheres that proliferate clonally from Flk1+/+ and Flk1−/− mice are of comparable size and cell number [160]. Similar studies demonstrate VEGF-A secreted from cerebral endothelial cells promotes migration of oligodendrocyte precursor cells (OPCs), but not proliferation, as treatment with a Flk-1 neutralizing antibody only affected OPC propagation [161]. Therefore, VEGF-A signaling may exert control over NSCs via the regulation of survival; this potential mechanism should be further explored, especially given that an internal autocrine role for VEGF-A in HSC survival has been demonstrated[162].

More recently, a direct requirement for VEGFR3 in neurogenesis has been established, and Vegfr3::YFP reporter mice demonstrate expression in NSC [155]. Interestingly, coexpression with VEGF-C along the walls of the lateral ventricle is also observed. Accordingly, an increase in neurogenesis is said to occur from VEGFR3+ NSC after VEGF-C stimulation, deletion of VEGFR3 in neural cells and SVZ astrocytes, as well as VEGFR3 inhibition via blocking antibodies, all lead to a reduction in neurogenesis. In vitro, VEGF-C treatment also increases BrdU incorporation in YFP+EGFR+ NSC [155].

5.2.2. BDNF & IGF

BDNF is secreted by EC and induces the differentiation of astrocyte precursors [147, 163], and in vivo has been shown to influence proliferation and differentiation of NSPC in adult neurogenic regions [121, 134]. As mentioned previously, in vivo experiments suggest that VEGF-induced secretion of BDNF from higher vocal center (HVC) capillary vasculature in the songbird brain results in newly born neuron recruitment. Interestingly, BDNF secretion in this region is quite high, as canary brain EC secrete an average of 1 ng BDNF/106 cells/24 h [121, 164]; a study of adult-derived human brain EC revealed a comparable amount of BDNF secretion [147]. In vitro, BDNF release from EC supports SVZ-derived neuron outgrowth, survival, and migration [147]. Although subependymal astrocytes also secrete BDNF, it may be sequestered at the cell surface; this is partly mediated by the truncated gp95 extracellular domain of TrkB, a high affinity receptor for BDNF, which prevents its release into the surrounding space [147]. This has been proposed to be a mechanism whereby regions of NSC expansion exclude BDNF, limiting its availability only to those areas supporting differentiation and maturation. Interestingly, while NSC and transit-amplifying cells express the low-affinity neurotrophin receptor p75, expression of TrkB is only found on lineage-restricted neuroblasts. Additionally, it has been suggested that BDNF acts in a positive feedback loop to reduce proliferation and increase neuroblast differentiation through the release of NO by NSPC [165, 166]. Thus, endothelial-derived BDNF appears to serve chemoattraction and survival roles for neuronal progenitors [167].

Studies of exercise-induced neurogenic cognitive enhancement in the dentate gyrus have linked BDNF with IGF-1 [168]. Exercise stimulates uptake of IGF-1 from the bloodstream in the hippocampus, leading to an increase in the number of BrdU+ hippocampal neurons as well as upregulation of BDNF mRNA and protein levels [169, 170]. The neurogenic effect of IGF-1 may be mediated in part through estrogen signaling, as estrogen antagonists reduce neurogenesis within the dentate gyrus [171]. From a clinical standpoint, IGF-1 may be involved in neurodegenerative disease progression, such as Alzheimer’s and stroke, where levels of circulating IGF-1 are altered [170].

5.2.3. PDGF

PDGF signaling has been shown to affect stem cell properties and lineage bias [98, 172]. Vascular EC secrete PDGF-B as a disulfide-linked homodimer (PDGF-BB), and via a specific positively charged C-terminal retention motif, it interacts with heparin sulfate proteoglycans within the ECM to aid in localized retention [173-176]. Specifically within the CNS, it regulates oligodendrocyte precursor cell number. Interestingly, PDGF-B is implicated in brain tumor formation, where activation of its signaling pathway is present in more than 80% oligodendrogliomas and 50–100% of astrocytomas[177]. Thus, identifying which cells respond to PDGF is crucial to elucidate mechanisms involved in these brain cancers.

In the SVZ, putative NSC and most GFAP+ cells have been shown to express PDGFRα, and become activated in the presence of PDGF-AA [178]. Accordingly, PDGF is reported to have mitogenic and differentiation actions on neural progenitor cells [179-181], and synergy with bFGF has been reported to enhance neurosphere generation [178]. After intracerebroventricular infusion of PDGF-AA, astrocyte-derived periventricular hyperplasias are formed, and increases in oligodendrogenesis are observed at the expense of olfactory bulb neurogenesis. While EGF infusion elicits a similar proliferative response in the SVZ, staining for PDGFRα and EGFR reveals expression in distinct populations, suggesting that they label stem cells and transit-amplifying progenitors, respectively. Conversely, conditional ablation of PDGRα in the SVZ decreases oligodendrogenesis while having little effect on neurogenesis [178]. Thus, PDGF signaling may play a role in maintaining the balance between neurogenesis and oligodendrogenesis.

5.2.4. SCF

SCF, also known as Kit ligand, has been reported to be expressed by a variety of cell types including vascular EC [182, 183]. Previous reports indicate that within the CNS, SCF/Kit-ligand signaling influences oligodendrocyte precursors prior to differentiation towards a myelinated phenotype. Although Kit belongs to the same class of tyrosine kinase receptors as PDGF receptors, their effects on NSPC are different. In nestin+ NSCs isolated from embryonic rat cortex, more than 93% express SCF. More recent studies demonstrate that SCF acts as a chemoattractant and survival factor for NSPCs during early stages of differentiation while having no effect on proliferation or differentiation [184-186].

5.2.5. PEDF

PEDF is secreted by a variety of cell types, and can interact with the ECM, most notably collagen-I [187-189]. Being the first soluble factor shown to selectively activate type B NSC, PEDF seems to contribute to stem cell maintenance within the neurogenic niche. In the adult mouse brain, expression is restricted to endothelial and ependymal cells, suggesting that PEDF is in fact a niche-derived signal. Accordingly, Western blot analysis on conditioned media from cultures indicate that PEDF is specifically secreted by endothelial and ependymal cells [144, 190, 191]. Aside from acting as a brake on cell cycle progression by promoting NSC self-renewal without affecting proliferation [192], recent evidence suggests an additional role in renewing symmetric divisions. Interestingly, PEDF has been implicated in regulating certain aspects of Notch signaling by modulating the NFκB pathway. The role of Notch signaling in NSC maintenance is well characterized [193], and NSC treated with PEDF upregulate Notch effectors Hes1 and Hes5, as well as the Sry-related HMG box-transcription factor Sox2 [194]. In cells with low levels of Notch signaling, PEDF enhances Notch-dependent transcription by relieving repression of Notch-responsive promoters by the transcriptional co-repressor N-CoR, thereby potentiating symmetric cell division [195]. Additionally, BrdU-labeled mice treated with PEDF display an increase in the number of BrdU+GFAP+ cells, and injection with a C-terminal blocking peptide to PEDF reveals no significant change in the number of BrdU+GFAP+ cells compared with vehicle-injected controls. Taken together, these data suggest that PEDF may not be a survival factor for NSC, and may instead serve to activate NSC by stimulating self-renewal [194].

5.2.6. Nitric Oxide (NO)

A variety of mechanisms have been proposed for NO regulation of NSPC, perhaps accounting for conflicting studies suggesting opposing roles on NSPC proliferation. Early reports demonstrated a role for NO in the repression of adult neurogenesis, as exposure to NOS inhibitors L-NAME and 7-NI increased neurogenesis in the dentate gyrus and SVZ [165, 166, 196, 197]. However, its effects seem to depend on the signaling pathway involved. Potentially through NO-induced S-nitrosylation of the EGFR [198], NO inhibits PI3K/Akt signaling to suppress NSPC proliferation, both in culture and in vivo [199]. However, bypassing the EGFR induces proliferation through activation of p21Ras, leading to an increase in activation levels of c-Myc, p90RSK and Elk-1, and subsequent reduction in p27Kip1 [200]. BDNF may be involved in this process as well, as its stimulatory effect on neuronal differentiation is blocked by L-NAME. Interestingly, NSC express and release NO, suggesting a feedback mechanism whereby NSC-produced NO induces production of BDNF from the vascular bed [201]. EC also produce NO via eNOS, and a decrease in SVZ cell proliferation and migration post-stroke is observed in eNOS-deficient mice. Interestingly, BDNF levels are also reduced in eNOS-/- ischemic mice, and BDNF treatment rescues the decrease in neurosphere formation, proliferation, and neurite outgrowth in cultured eNOS-/- neurospheres [202].

5.2.7. Vascular ECM: Laminins, collagens, fractones

The ECM is an integral component of the NSC niche, regulating signaling by providing, storing, and compartmentalizing growth factors and cytokines indispensable for proliferation, differentiation and adhesion. Within the SVZ, a unique basal lamina, rich in laminins, collagen-1 and collagen IV, extends from perivascular cells as ‘fractones’ [203]. Each fractone consists of a base, attached to the perivascular cell, a stem that crosses the SVZ, and bulbs that terminate just underneath the ependymal layer [204]. The branched configuration of fractones has been suggested to enable sequestration and subsequent presentation of growth factors and other signaling molecules to stem cells and progenitors to regulate their proliferation, activation, and differentiation within the niche [205].

Other important ECM molecules secreted by niche cells are laminin and fibronectin, both of which have been implicated in neural stem cell growth, differentiation, and migration. In addition to promoting neuroepithelial proliferation and differentiation during development, they also function as permissive substrates, supporting the migration of cerebellar neural precursors in vitro and neural progenitors through the RMS in vivo [206]. Most recently, the importance of laminin–integrin interactions within the SVZ support a role in migration, spreading and proliferation of NSPC [37]. Several in vitro studies have highlighted a critical role for β1-integrin in mediating multiple effects of ECM on NSC in a temporally and spatially controlled manner. For example, genetic ablation of β1-integrin results in reduced neural progenitor proliferation, increased cell death, and impairment of cell migration on different ECM substrates [207]. In β1-integrin-deficient neurospheres, β1-integrin signaling is not required for NSC maintenance, and instead seems to cooperate with growth factor signaling to regulate progenitor number [208]. In vivo, the role of laminins in migration and recruitment are critical, as injection of intact laminin and peptide infusion mimicking the E8 domain of the laminin α chain dramatically redirect neuroblast migration towards the site of administration. Interestingly, inhibiting the α6 or β1 subunits with antibodies also recapitulates the migratory defect without causing neuroblast death [209].

Collagen IV and chondroitin sulfate proteoglycans (CSPG) are also present in the microenvironment, and have been demonstrated to exert control over proliferation, leading to differentiation. While collagen IV inhibits proliferation of rat NSPCs and promotes differentiation into neurons [210], treatment of neurospheres or telencephalic ventricles with enzymes degrading CSPG glycosminoglycans leads to a reduction in cell proliferation and self-renewal of radial glia; interestingly, the increase in astrocyte formation is at the expense of neuronal differentiation [211]. Additionally, sulfation of chondroitin sulfate polymers in vitro modulates the activities and effects of various growth and morphogenetic factors that control NSC proliferation, maintenance, and differentiation [212].

5.3. Other putative endothelial-derived niche effectors

5.3.1. FGF-2

FGF-2 (aka (b)FGF) is detected in the endothelium of tumor capillaries in vivo, as well as at sites of vessel branching within the basal lamina of capillaries. In vitro studies suggest significant amounts of FGF-2 can also localize to the ECM in cell culture. Normally found to be extracellular, FGF-2 is reported to modulate cell function in an autocrine manner, and depending on the molecular weight isoform, may or may not be secreted; secreted FGF acts through intracellular signaling mechanisms [213]. While EC can secrete this potent angiogenic factor [214] to regulate proliferation, migration and differentiation, type B NSC respond to [113, 215-218] and express the corresponding receptor [178, 219, 220]. Within the CNS, FGF-2 has been shown to affect neurogenesis and proliferation of cortical progenitors [220-222]. Interestingly, FGF-2 infusion increases adult SVZ proliferation while decreasing the number of newly born neurons, suggesting that FGF-2 serves to maintain SVZ self-renewal [223]. In fact, Fgf-2 knockout mice display a decrease in olfactory bulb size, presumably owing to attentuated output from neurogenic regions. Although FGF-2 can promote NSC proliferation, it does not act alone to maintain self-renewal, and must work with other factors to accomplish this [37]. In addition to inducing VEGF expression in EC, FGF-2 can prime neural precursor responsiveness towards EGF [218].

5.3.2. EGF & Betacellulin

While the specific cell type(s) expressing and secreting EGF remains unidentified within the adult NSC niche, several reports suggest an EC orgin. Affymetrix microarray analysis has revealed that human dermal microvascular EC express EGF, and that this expression is further upregulated in coculture with head and neck squamous cell carcinoma cells [224]. Similarly, an antibody-based human cytokine array has demonstrated that EGF is expressed and secreted by dermal microvascular endothelial cells with or without VEGF stimulation, suggesting basal expression of EGF within some EC [146]. Within the SVZ, receptors for EGF are predominantly expressed by the type C transit-amplifying cells apposed to capillaries. Furthermore, EGFR expression can be further induced by SDF-1 and PEDF [34, 85, 225, 226]. Intraventricular infusion of EGF increases the number of type B NSC contacting the ventricle [219], and leads to transit-amplifying cell proliferation while arresting neuroblast production. In vitro, EGF stimulates neurosphere generation from transit-amplifying cells, and is said to cause reversion to a more ‘stem-like’ phenotype [219]. Curiously, transit-amplifying cells with elevated EGFR signaling also show non-cell autonomous defects in Notch signaling, leading to elevated Numb levels in the stem compartment [227].

Recently, another member of the EGF family, BTC, has been shown to play a critical role in SVZ regulation. mRNA transcripts for BTC are detectable in EC, and immunofluorescent analysis reveals protein expression in EC of microcapillaries and in the choroid plexus, with the latter demonstrating greater expression. After intraventricular infusion, NSC and neuroblast compartments are expanded, promoting neurogenesis both in the olfactory bulb and the dentate gyrus. Defects in neuroblast regeneration are observed post cytosine-β-arabinofuranoside (Ara-C) infusion in Btc-null mice in comparison to wild-type littermates. Although related to EGF, its effects in the SVZ are slightly different, and it has been suggested that its ability to act on distinct receptors expressed on NSC and neuroblasts, EGFR and Erb4 respectively, may account for these differential effects.

5.3.3. BMPs & LIF & IL-6

In addition to high levels of BMP2 and BMP4 production in astroglia within the SVZ, it has been demonstrated that brain EC can act as potential sources of BMP. mRNA transcripts for BMP2 and BMP4 were found in the bEnd.3 endothelial cell line, as well as in primary brain EC. Furthermore, BMP4 protein was also detected in these brain EC [228]. Shown to counteract neurogenesis in vitro and in vivo [229-231], BMP signaling increases astrocyte formation, possibly through activation of transcriptional regulators of Smads to control cell-cycle exit. Indeed, when embryonic and adult NSPC are cocultured with brain EC, the canonical BMP/Smad pathway becomes activated to reduce proliferation and induce NSPC cell-cycle exit in the presence of EGF and FGF-2 [228]. LIF and IL-6 belong to the cohort of endothelial-secreted factors that promote self-renewal of adult NSC [232], and when synergize with BMP factors to promote self-renewal of embryonic stem cells through activation of gp130-mediated STAT signaling, which induces astrogenesis [232, 233].

5.3.4. SDF-1 & growth-related oncogene-α & angiopoietin

A chemokine previously shown to direct migration of leukocytes during inflammation, SDF-1/CXCL12 signaling via its CXCR4 receptor also provides migratory cues for NSPC recruitment from the lateral ventricle to the nascent dentate gyrus during CNS development; interestingly, SDF-1/CXCR4 expression by EC and neurons persists in the adult dentate gyrus. In the SVZ, neural cells express CXCR4 while ependymal cells and vascular EC express SDF-1 [226]. Neuroblasts expressing CXCR4 migrate towards and are attracted to activated EC of cerebral vessels that secrete SDF-1α [234-238]. While neurospheres express CXCR4, human cerebral EC have been shown to secrete growth-related oncogene-α, also a ligand for CXCR4 [239]. More recently, evidence of progenitor homing to SVZ EC in a SDF1/CXCR4-dependent manner has been demonstrated, where SDF1 upregulates EGFR and α6-integrin in activated NSC and transit amplifying cells, thereby enhancing activation state and the binding to laminin on resident vessels. SDF1 was also shown to increase the motility of migrating neuroblasts towards the olfactory bulb [34, 226].

Recent reports also suggest shared receptor/cytokine signaling between NSC and the vasculature concerning growth related CXCR4/oncogene-α and Ang-1/Tie2 [240, 241]. Ang-1 can be expressed by EC, as well as mural cells, and seems to be upregulated poststroke. While also having a general neuroprotective effect on the nervous system, it has been shown to directly regulate stem cell differentiation and migration through the Tie2 and CXCR4 receptors [235, 237, 242-244].

5.3.5. TGF-β1

Latent TGF-β1 is secreted by EC, pericytes, glia and neurons. Reported to induce VEGF expression by vascular EC and gliomas [245, 246], TGF-β1 serves as an important neurogenic growth factor. Produced in a latent form in mesenchymal and epithelial cell types, EC and mural cells have also been shown to produce a latent form of TGF-β1 which can be activated in endothelial cell-mural cell cocultures [247, 248]. Because Tgf-β1 knockout mouse models demonstrate a reduced potential for neuron survival [249], and transgenic mouse models overexpressing Tgf-β1 under control of the GFAP promoter show a reduction in NSCP proliferation [250], it is believed that TGF-β1 has no impact on NSP identity or on differentiation. Rather, it is believed to affect proliferative potential, as demonstrated by an arrest in the G0/G1 phase of the cell cycle [251]. In cell culture, NSC and progenitors express TGFβRI, II and III, and TGF-β1 decreases the expansion of these cells in a dose-dependent manner [252].

5.3.6. Ephs and ephrins

Belonging to a family of receptor tyrosine kinases and associated transmembrane ligands, Ephrins and Eph receptors have established roles in vascular development. However, more recent data suggest both a role for Eph receptor and ephrin ligand interaction within the CNS, and this interaction can occur between endothelial and nonvascular tissues. For example, during development, the close proximity of EphB3/4 on intersomitic vessels with ephrin-B1/B2 of somites seems to imply bidirectional communication [253]. Within the SVZ, EphA7 seems to localize to ependymal cells and astrocytes. Interestingly, the cells immunoreactive for EphA7 also express nestin, a marker associated with NSC. Additionally, ephrin-B2/3 is localized to SVZ astrocytes. By contrast, ephrin-A2 is predominantly expressed on transit-amplifying cells and neuroblasts [254, 255]. Although ephrin-B2 is not cell type exclusive within the SVZ, it has been shown to selectively mark arterial endothelium in the adult, as well as surrounding smooth muscle cells and pericytes [256]. While EphA7 and ephrin-A2 negatively regulate NSPC proliferation, EphB1–2/EphA4 and ephrin-B2/3 direct neuroblast migration and directly or indirectly regulate NSPC proliferation. Interestingly, infusion of antibody-clustered ephrin-B2-Fc or EphB2-Fc into the lateral ventricle increases SVZ proliferation, suggesting that B-class ephrins and Ephs may promote proliferation [254, 255, 257]. A correlation between EphB2 and Notch signaling has also been proposed, wherein EphB2 acts downstream of Notch to maintain ependymal identity under homeostatic conditions, while regulating conversion to astrocytes after injury [258].

5.4. Circulating effectors:

5.4.1. Erythropoietin & prolactin

Systemic transport of erythropoietins and prolactins via blood circulation has been demonstrated to have effects within the CNS. Prolactin, in cooperation with TGF-α, promotes SVZ proliferation and neuronal differentiation. It has been proposed that prolactin serves as an important contributor to the increase in neurogenesis during pregnancy [259]; however, the responsiveness to prolactin within the dentate gyrus is negligible [259, 260]. Although erythropoietin synthesis can be activated in astrocytes and neurons [261-263], it is also possible that circulating erythropoietin, from the kidneys, can cross the BBB to exert neuroprotective effects. Significant amounts of the erythropoietin receptor are localized to the surface of EC and within caveoli [264, 265], and systemic administration of erythropoietin has been shown to penetrate the BBB as an intact molecule [266]. These observations certainly suggest that erythropoietin can reach the brain; however, the precise mechanism mediating this transport is unknown. Erythropoietin has been shown to stimulate NSPC production and prevent apoptosis during embryonic development. Additionally, it serves as a paracrine neuroprotective mediator of ischemia in the brain [267], and erythropoietin-activated EC promote the migration of neuroblasts through the secretion of MMP-2 and 9. [268]. Thus, further investigation of the penetrance and potential function of erythropoietin in the adult NSC niche is warranted.


6. Conclusions

Its remarkable ability to penetrate throughout the entire body to regulate and respond to distinct microenvironments simultaneously has truly earned the vasculature the term of ‘master regulator’. It plays a crucial role in embryonic and adult neurogenesis, where its secretion and/or systemic circulation of growth factors, serves to regulate the growth and behavior of stem and progenitor cells. Although a handful of signaling molecules have been identified thus far, it is likely that there are many more unidentified effectors that influence NSC behavior. From a neuro-regenerative perspective, identifying factors responsible for modulating specific stem cell behaviors is crucial, whether the goal is preventing further tissue loss or potentiating endogenous repair mechanisms. Towards this goal, stem cell-based therapies offer the intriguing possibility of accomplishing both. Therefore, understanding the intrinsic and extrinsic mechanisms responsible for modulating NSPC behavior will be critical for the development of more targeted therapies. As mounting evidence points to a strong interdependent relationship between neurogenesis and the vasculature, therapies aimed at targeting both compartments hold great promise.



This work was supported by NIH R01-HL077675 and R01-HL096360 to KKH.


  1. 1. AitsebaomoJet alBrothers and sisters: molecular insights into arterial-venous heterogeneity. Cir Res, 2008929939
  2. 2. AirdW. CPhenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res, 2007158
  3. 3. AirdW. CPhenotypic heterogeneity of the endothelium: II. Representative vascular beds. Cir Res, 2007174190
  4. 4. AirdW. CEndothelium in health and disease. Pharmacol Rep, 2008139143
  5. 5. GirouardHand I. C., Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Genet, 2006328335
  6. 6. WiederholdK. Hand S. UBielserWJrVeteauM. JHunzikerOThree-dimensional reconstruction of brain capillaries from frozen serial sections. Microvasc Res, 1976175180
  7. 7. AtkinsG. BJainM. Kand HamikAEndothelial differentiation: molecular mechanisms of specification and heterogeneity. Arterioscler Thromb Vasc Biol, 201114761484
  8. 8. WolburgHand M. ANoellSWolburg-buchholzKFallier-beckerP., Brain endothelial cells and the glio-vascular complex. Cell Tissue Res, 20097596
  9. 9. BärTThe vascular system of the cerebral cortex. Adv Anat Embryol Cell Biol, 1980I-VI): 162
  10. 10. KieckerCand ALumsdenRecent advances in neural development. F1000 Biol Rep, 20091
  11. 11. CianiLand P. CSalinasWNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci, 2005351362
  12. 12. De RobertisE. Met alThe establishment of Spemann’s organizer and patterning of the vertebrate embryo. Nat Rev Genet, 2000171181
  13. 13. MadenMRetinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci, 2007755765
  14. 14. MasonIInitiation to end point: the multiple roles of fibroblast growth factors in neural development. Nat Rev Neurosci, 2007583596
  15. 15. NiehrsCRegionally specific induction by the Spemann-Mangold organizer. Nat Rev Genet, 2004425434
  16. 16. RhinnMAPickerand MBrandGlobal and local mechanisms of forebrain and midbrain patterning. Curr Opin Neurobiol, 2006512
  17. 17. SternC. Det alHead-tail patterning of the vertebrate embryo: one, two or many unresolved problems? Int J Dev Biol, 2006315
  18. 18. WilsonS. Wand CHouartEarly steps in the development of the forebrain. Dev Cell, 2004167181
  19. 19. NoctorS. CVMartinez-cerdenoand A. RKriegsteinContribution of intermediate progenitor cells to cortical histogenesis. Arch Neurol, 2007639642
  20. 20. AnthonyT. Eet alRadial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron, 2004881890
  21. 21. NadarajahBand G. JBrunstromJ. EWongR. OPearlmanAL., Two modes of radial migration in early development of the cerebral cortex. Nat Neurosci, 2001143150
  22. 22. ParnavelasJ. GThe origin of cortical neurons. Braz J Med Biol Res, 200214231429
  23. 23. HaubensakWand D. WAttardoAHuttnerWB., Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis. Proc Natl Acad Sci U S A., 200431963201
  24. 24. MarínOand R. J. L. , ALongremarkable journey: tangential migration in the telencephalon. Nat Rev Neurosci, 2001780790
  25. 25. GalileoD. Set alNeurons and glia arise from a common progenitor in chicken optic tectum: demonstration with two retroviruses and cell type-specific antibodies. Proc Natl Acad Sci U S A., 1990458462
  26. 26. GoldenJ. Aand C. CL., Clones in the chick diencephalon contain multiple cell types and siblings are widely dispersed. Development, 19966578
  27. 27. GrayG. Eand M. JGloverJ. CSanesJR., Radial arrangement of clonally related cells in the chicken optic tectum: lineage analysis with a recombinant retrovirus. Proc Natl Acad Sci U S A., 198873567360
  28. 28. LeberS. Mand S. JBreedloveS. MLineagearrangement, and death of clonally related motoneurons in chick spinal cord. J Neurosci, 199024512462
  29. 29. TurnerD. Land C. CL., A common progenitor for neurons and glia persists in rat retina late in development. Nature, 1987131136
  30. 30. WalshCand C. CL., Widespread dispersion of neuronal clones across functional regions of the cerebral cortex. Science, 1992434440
  31. 31. LuskinM. Band S. JPearlmanAL, Cell lineage in the cerebral cortex of the mouse studied in vivo and in vitro with a recombinant retrovirus. Neuron, 1988635647
  32. 32. PriceJand T. L., Cell lineage in the rat cerebral cortex: a study using retroviral-mediated gene transfer. Development, 1988473482
  33. 33. ShenQand K. EWangYLinGChuangS. MGoderieS. KRoysamBTempleS., Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell, 2008289300
  34. 34. TavazoieMand S. -V. VVan Der VekenLLouissaintMColonnaLZaidiBGarcia-verdugoJ. MDoetschF., A specialized vascular niche for adult neural stem cells. Cell Stem Cell, 2008279288
  35. 35. NieKZMolnarand F. GSzeleProliferation but not migration is associated with blood vessels during development of the rostral migratory stream. Dev Neurosci, 2010163172
  36. 36. DanemanRet alThe mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One, 2010e13741
  37. 37. ShenQand J. LGoderieS. KKaranthNSunYAbramovaNVincentPPumigliaKTempleS., Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. 304, 2004
  38. 38. HoganK. Aet alThe neural tube patterns vessels developmentally using the VEGF signaling pathway. Development, 200415031513
  39. 39. JavaherianAand AKriegsteinA stem cell niche for intermediate progenitor cells of the embryonic cortex. Cereb Cortex, 2009Suppl 1: i70i77
  40. 40. StubbsDet alNeurovascular congruence during cerebral cortical development. Cereb Cortex, 2009Suppl 1: i32i41
  41. 41. VasudevanAet alCompartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain. Nat Neurosci, 2008429439
  42. 42. KurzHPhysiology of angiogenesis. J Neurooncol, 20001735
  43. 43. PlateK. HMechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol, 1999313320
  44. 44. GreenbergD. Aand KJinFrom angiogenesis to neuropathology. Nature, 2005954959
  45. 45. HirumaTYNakajimaand HNakamuraDevelopment of pharyngeal arch arteries in early mouse embryo. J Anat, 20021529
  46. 46. NoctorS. Cet alNeurons derived from radial glial cells establish radial units in neocortex. Nature, 2001714720
  47. 47. MiyataTet alAsymmetric inheritance of radial glial fibers by cortical neurons. Neuron, 2001727741
  48. 48. TabataHSYoshinagaand KNakajimaCytoarchitecture of mouse and human subventricular zone in developing cerebral neocortex. Exp Brain Res. 216(2): 161168
  49. 49. NoctorS. Cet alCortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci, 2004136144
  50. 50. Aaku-sarasteEHellwigAand HuttnerW. BLoss of occludin and functional tight junctions, but not ZO-1, during neural tube closure--remodeling of the neuroepithelium prior to neurogenesis. Dev Biol, 1996664679
  51. 51. BancroftMand BellairsRDifferentiation of the neural plate and neural tube in the young chick embryo. A study by scanning and transmission electron microscopy. Anat Embryol, 1975309335
  52. 52. LehtinenM. Kand C. AWalshNeurogenesis at the brain-cerebrospinal fluid interface. Annu Rev Cell Dev Biol. 27: 653679
  53. 53. KriegsteinAand AAlvarez-buyllaThe glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci, 2009149184
  54. 54. TavernaEand W. BHuttnerNeural progenitor nuclei IN motion. Neuron, 2010906914
  55. 55. TakahashiTR. SNowakowskiand V. SCavinessJr., The leaving or Q fraction of the murine cerebral proliferative epithelium: a general model of neocortical neuronogenesis. J Neurosci, 199661836196
  56. 56. KosodoYet alAsymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J, 200423142324
  57. 57. RakicPA century of progress in corticoneurogenesis: from silver impregnation to genetic engineering. Cereb Cortex, 2006Suppl 1: i317
  58. 58. TarabykinVet alCortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. Development, 200119831993
  59. 59. KriegsteinASNoctorand VMartinez-cerdenoPatterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nat Rev Neurosci, 2006883890
  60. 60. Martinez-cerdenoVS. CNoctorand A. RKriegsteinThe role of intermediate progenitor cells in the evolutionary expansion of the cerebral cortex. Cereb Cortex, 2006Suppl 1: i152i161
  61. 61. NoctorS. CVMartinez-cerdenoand A. RKriegsteinDistinct behaviors of neural stem and progenitor cells underlie cortical neurogenesis. J Comp Neurol, 20082844
  62. 62. PontiousAet alRole of intermediate progenitor cells in cerebral cortex development. Dev Neurosci, 20082432
  63. 63. TakahashiTR. SNowakowskiand V. SCavinessJr., Early ontogeny of the secondary proliferative population of the embryonic murine cerebral wall. J Neurosci, 199560586068
  64. 64. LoisCand AAlvarez-buyllaProliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci U S A, 199320742077
  65. 65. FietzS. Aet alOSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat Neurosci, 2010690699
  66. 66. HansenD. Vet alNeurogenic radial glia in the outer subventricular zone of human neocortex. Nature, 2010554561
  67. 67. ReilloIet alA role for intermediate radial glia in the tangential expansion of the mammalian cerebral cortex. Cereb Cortex, 201116741694
  68. 68. ShitamukaiADKonnoand FMatsuzakiOblique radial glial divisions in the developing mouse neocortex induce self-renewing progenitors outside the germinal zone that resemble primate outer subventricular zone progenitors. J Neurosci, 201136833695
  69. 69. WangXet alA new subtype of progenitor cell in the mouse embryonic neocortex. Nat Neurosci, 2011555561
  70. 70. FarinAet alTransplanted glioma cells migrate and proliferate on host brain vasculature: a dynamic analysis. Glia, 2006799808
  71. 71. GoldmanS. Aand ZChenPerivascular instruction of cell genesis and fate in the adult brain. Nat Neurosci, 201113821389
  72. 72. Alvarez-buyllaAJ. MGarcia-verdugoand A. DTramontinA unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci, 2001287293
  73. 73. MerkleF. Tet alRadial glia give rise to adult neural stem cells in the subventricular zone. Proc Natl Acad Sci U S A, 20041752817532
  74. 74. MirzadehZet alNeural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell Stem Cell, 2008265278
  75. 75. ShenQet alAdult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell, 2008289300
  76. 76. AltmanJand S. ABayerMosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells. J Comp Neurol, 1990325342
  77. 77. EckenhoffM. Fand PRakicRadial organization of the hippocampal dentate gyrus: a Golgi, ultrastructural, and immunocytochemical analysis in the developing rhesus monkey. J Comp Neurol, 1984121
  78. 78. HanY. Get alHedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci, 2008277284
  79. 79. BreunigJ. Jet alPrimary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc Natl Acad Sci U S A, 20081312713132
  80. 80. MerkleF. TZMirzadehand AAlvarez-buyllaMosaic organization of neural stem cells in the adult brain. Science, 2007381384
  81. 81. TakahashiTand C. V. JNowakowskiR. SInterkineticand migratory behavior of a cohort of neocortical neurons arising in the early embryonic murine cerebral wall. J Neurosci, 199657625776
  82. 82. NadarajahBand E. WJonesA. MParnavelasJG., Differential expression of connexins during neocortical development and neuronal circuit formation. J Neurosci, 199730963111
  83. 83. BittmanK. Sand LoTurco JJ, Differential regulation of connexin 26 and 43 in murine neocortical precursors. Cereb Cortex, 1999188195
  84. 84. BittmanKet alConnexin expression in homotypic and heterotypic cell coupling in the developing cerebral cortex. J Comp Neurol, 2002201212
  85. 85. TavazoieMet alA specialized vascular niche for adult neural stem cells. Cell Stem Cell, 2008279288
  86. 86. LuoJand L. JDanielsS. BNottiR. QConoverJC., The aging neurogenic subventricular zone. Aging Cell, 2006139152
  87. 87. LoisCand A. -B. ALong-distanceneuronal migration in the adult mammalian brain. Science, 199411451148
  88. 88. BieblMet alAnalysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neurosci Lett, 20001720
  89. 89. LuskinM. BRestricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron, 1993173189
  90. 90. MennBand Y. CGarcia-verdugoJ. MGonzalez-perezORowitchDAlvarez-buyllaA., Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci, 200679077918
  91. 91. SeriBand C. -M. LGarcía-verdugoJ. MMcewenB. SAlvarez-buyllaA., Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol, 2004359378
  92. 92. RiquelmeP. Aand D. FDrapeauE, Brain micro-ecologies: neural stem cell niches in the adult mammalian brain. Philos Trans R Soc Lond B Biol Sci, 2008123137
  93. 93. SeabergR. Mand v.d.K. D., Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci, 200217841793
  94. 94. ClarkeLand v.d.K. D., The Adult Mouse Dentate Gyrus Contains Populations of Committed Progenitor Cells that are Distinct from Subependymal Zone Neural Stem Cells. Stem Cells, 201114481458
  95. 95. DoetschFand A. -B. AGarcía-verdugoJM, Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci, 199750465061
  96. 96. MorsheadC. Mand C. CReynoldsB. AMcburneyM. WStainesW. AMorassuttiDWeissSVan Der KooyD., Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron, 199410711082
  97. 97. De Pina-benabouM. Hand S. DSrinivasMScemesE., Calmodulin kinase pathway mediates the K+-induced increase in Gap junctional communication between mouse spinal cord astrocytes. J Neurosci, 200166356643
  98. 98. IhrieR. Aand A. -B. ALake-frontproperty: a unique germinal niche by the lateral ventricles of the adult brain. Neuron, 2011674686
  99. 99. MirzadehZand S. -N. MMerkleF. TGarcia-verdugoJ. MAlvarez-buyllaA., Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. Cell stem Cell, 2008265278
  100. 100. DoetschFA niche for adult neural stem cells. Curr Opin Gen Dev, 2003543550
  101. 101. PalmerT. Dand G. FWillhoiteAR, Vascular niche for adult hippocampal neurogenesis. J Comp Neurol, 2000479494
  102. 102. LieD. Cand C. SSongHMingG. LGageFH., Neurogenesis in the adult brain: new strategies for central nervous system diseases. Annu Rev Pharmacol Toxicol, 2004399421
  103. 103. CoskunVand B. BWuHTsaoSKimKZhaoJBiancottiJ. CHutnickLKruegerR. CJrFanGDe VellisJSunY. ECD133+ neural stem cells in the ependyma of mammalian postnatal forebrain. Proc Natl Acad Sci U S A., 200810261031
  104. 104. MeletisKand C. MBarnabé-heiderFEvergrenETomilinNShupliakovOFrisénJ., Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol, 2008e182
  105. 105. BeckervordersandforthRet alIn vivo fate mapping and expression analysis reveals molecular hallmarks of prospectively isolated adult neural stem cells. Cell Stem Cell, 2010744758
  106. 106. LuskinM. Band S. BZigovaTStewartRR., Neuronal progenitor cells derived from the anterior subventricular zone of the neonatal rat forebrain continue to proliferate in vitro and express a neuronal phenotype. Nol Cell Neurosci, 1997351366
  107. 107. García-verdugoJ. Met alArchitecture and cell types of the adult subventricular zone: in search of the stem cells. J Neurobiol, 1998234248
  108. 108. KelschWand L. CMosleyC. PLoisC., Distinct mammalian precursors are committed to generate neurons with defined dendritic projection patterns. PLoS Biol, 2007e300
  109. 109. KohwiMand L. JPetryniakM. AEkkerMObataKYanagawaYRubensteinJ. LAlvarez-buyllaA., A subpopulation of olfactory bulb GABAergic interneurons is derived from Emx1- and Dlx5/6-expressing progenitors. J Neurosci, 200768786891
  110. 110. MerkleF. Tand A. -B. AMirzadehZ, Mosaic organization of neural stem cells in the adult brain. Science, 2007381384
  111. 111. VenturaR. Eand G. JE., Dorsal radial glia generate olfactory bulb interneurons in the postnatal murine brain. J Neurosci, 200742974302
  112. 112. YoungK. Mand K. NFogartyMRichardsonWD., Subventricular zone stem cells are heterogeneous with respect to their embryonic origins and neurogenic fates in the adult olfactory bulb. J Neurosci, 200782868296
  113. 113. GageF. Het alSurvival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A., 19951187911883
  114. 114. KuhnH. Gand G. FDickinson-ansonH, Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci, 199620272033
  115. 115. TempleSThe development of neural stem cells. Nature, 2001112117
  116. 116. RahpeymaiYand W. UHietalaM. AFotheringhamADaviesINilssonA. KZwirnerJWetselR. AGerardCPeknyMPeknaMComplementa novel factor in basal and ischemia-induced neurogenesis. EMBOJ, 200613641374
  117. 117. ShingoTand S. TSorokanS. TWeissS., Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci, 200197339743
  118. 118. ThoredPand A. AWoodJCammengaJKokaiaZLindvallOLong-termneuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke, 200730323039
  119. 119. YamashitaTand H. A. PNinomiyaMGarcía-verdugoJ. MSunaboriTSakaguchiMAdachiKKojimaTHirotaYKawaseTArakiNAbeKOkanoHSawamotoK., Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci, 200666276636
  120. 120. OhabJ. Jand B. AFlemingSCarmichaelST., A neurovascular niche for neurogenesis after stroke. J Neurosci, 20061300713016
  121. 121. Louissaint A Jr and LC. Rao S, Goldman SA., Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron, 2002945960
  122. 122. MonjeM. Land F. JMizumatsuSPalmerTD., Irradiation induces neural precursor-cell dysfunction. Nat Med, 2002955962
  123. 123. JinKand S. YZhuYMaoX. OXieLGreenbergDA., Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A., 20021194611950
  124. 124. WurmserA. Eand G. FPalmerT. DNeuroscienceCellular interactions in the stem cell niche. Science, 200412531255
  125. 125. ShimaD. Tand M. C., Vascular developmental biology: getting nervous. Curr Opin Genet Dev, 2000536542
  126. 126. DingYand L. XLiJDingY. HLaiQRafolsJ. APhillisJ. WClarkJ. CDiazFG., Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience, 2004583591
  127. 127. VasconcellosJ. Pand S. RMeloM. BBressanimN. CCostaF. FCostaVP., A novel mutation in the GJA1 gene in a family with oculodentodigital dysplasia. Arch Ophthalmol, 200514221426
  128. 128. BarneaAand NottebohmFSeasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees. Proc Natl Acad Sci U S A., 199411217112121
  129. 129. KempermannGand G. FKuhnHG, More hippocampal neurons in adult mice living in an enriched environment. Nature, 1997493495
  130. 130. KempermannGand G. FKuhnH. GExperience-inducedneurogenesis in the senescent dentate gyrus. J Neurosci, 199832063212
  131. 131. WhitmanM. Cet alBlood vessels form a migratory scaffold in the rostral migratory stream. J Comp Neurol, 200994104
  132. 132. BovettiSet alBlood vessels form a scaffold for neuroblast migration in the adult olfactory bulb. J Neurosci, 200759765980
  133. 133. YangX. TY. YBiand D. FFengFrom the vascular microenvironment to neurogenesis. Brain Res Bull, 201117
  134. 134. LeventhalCand R. DRafiiSShaharAGoldmanSA., Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol Cell Neurosci, 1999450464
  135. 135. WolswijkGand N. MRiddleP. NPlatelet-derivedgrowth factor is mitogenic for O-2Aadult progenitor cells. Glia, 1991495503
  136. 136. BarresB. Aet alMultiple extracellular signals are required for long-term oligodendrocyte survival. Development, 1993283295
  137. 137. CameronH. AHazelT. Gand MckayR. DRegulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol, 1998287306
  138. 138. ParkJ. Aand K. SChoiK. SKimKW., Coordinated interaction of the vascular and nervous systems: from molecule- to cell-based approaches. Biochem Biophys Res Commun, 2003247253
  139. 139. ParisFand K. AFuksZCapodieciPJuanGEhleiterDHaimovitz-friedmanACordon-cardoCKolesnickR., Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science, 2001293297
  140. 140. Garcia-barrosMet alTumor response to radiotherapy regulated by endothelial cell apoptosis. Science, 200311551159
  141. 141. GuzmanRand D. L. A. ABlissTMoseleyMPalmerTSteinbergG., Neural progenitor cells transplanted into the uninjured brain undergo targeted migration after stroke onset. J Neurosci Res, 2008873882
  142. 142. NakagomiNet alEndothelial cells support survival, proliferation, and neuronal differentiation of transplanted adult ischemia-induced neural stem/progenitor cells after cerebral infarction. Stem Cells, 200921852195
  143. 143. TengHand W. LZhangZ. GZhangR. LZhangLMorrisDGreggS. RWuZJiangALuMZlokovicB. VChoppM., Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke. J Cereb Blood Flow Metab, 2008764771
  144. 144. Ramírez-castillejoCand A. -A. CSánchez-sánchezFFerrónS. RAroca-aguilarJ. DSánchezPMiraHEscribanoJFariñasI., Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat Neurosci, 2006331339
  145. 145. CaoLet alVEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet, 2004827835
  146. 146. SchmidtN. Oand M. MKoederDMuellerF. JAboodyK. SKimS. UBlackP. MCarrollR. SWestphalMLamszusK., Vascular endothelial growth factor-stimulated cerebral microvascular endothelial cells mediate the recruitment of neural stem cells to the neurovascular niche. Brain Res, 20092437
  147. 147. MiHand B. BHaeberleH, Induction of astrocyte differentiation by endothelial cells. J Neurosci, 200115381547
  148. 148. GoldbergJ. Sand K. KHirschiDiverse roles of the vasculature within the neural stem cell niche. Regen Med, 2009879897
  149. 149. ZhangHet alVEGF is a chemoattractant for FGF-2-stimulated neural progenitors. J Cell Biol, 200313751384
  150. 150. SchänzerAand W. DWachsF. PAckerTCooper-kuhnCBeckHWinklerJAignerLPlateK. HKuhnHG., Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol, 2004237248
  151. 151. MengHet alBiphasic effects of exogenous VEGF on VEGF expression of adult neural progenitors. Neurosci Lett, 200697101
  152. 152. WadaTand E. MHaighJ. JHitoshiSChaddahRRossantJNagyAVan Der KooyD., Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival. J Neurosci, 200668036812
  153. 153. ManiNet alVascular endothelial growth factor enhances migration of astroglial cells in subventricular zone neurosphere cultures. J Neurosci Res, 2010248257
  154. 154. WittkoI. Met alVEGFR-1 regulates adult olfactory bulb neurogenesis and migration of neural progenitors in the rostral migratory stream in vivo. J Neurosci, 200987048714
  155. 155. CalvoC. Fet alVascular endothelial growth factor receptor 3 directly regulates murine neurogenesis. Genes Dev, 2011831844
  156. 156. LeeH. Jet alHuman neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS One, 2007e156
  157. 157. SunYet alVEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest, 200318431851
  158. 158. MaurerM. Hand F. R. JTrippsW. KKuschinskyW., Expression of vascular endothelial growth factor and its receptors in rat neural stem cells. Neurosci Lett, 2003165168
  159. 159. ChowJand F. SOgunsholaOLiYMentL. RMadriJ. AAstrocyte-derivedVEGF mediates survival and tube stabilization of hypoxic brain microvascular endothelial cells in vitro. Brain Res Dev Res, 2001123132
  160. 160. LucittiJ. Land H. CJonesE. AChenJFraserS. EDickinsonME., Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development, 200733173326
  161. 161. HayakawaKet alCerebral endothelial derived vascular endothelial growth factor promotes the migration but not the proliferation of oligodendrocyte precursor cells in vitro. Neurosci Lett, 20124246
  162. 162. GerberH. Pet alVEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature, 2002954958
  163. 163. ShahN. Mand A. DGrovesAK, Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell, 1996331343
  164. 164. NottebohmFThe neural basis of birdsong. PLoS Biol, 2005e164
  165. 165. ChengAand C. JWangSRaoM. SMattsonMP., Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol, 2003319333
  166. 166. PackerM. Aand B. AStasivYChmielnickiEGrinbergAWestphalHGoldmanS. AEnikolopovG., Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci U S A., 200395669571
  167. 167. SnapyanMet alVasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling. J Neurosci, 200941724188
  168. 168. VaynmanSand G. -P. FYingZ, Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience, 2003647657
  169. 169. DingQand A. MVaynmanSYingZGomez-pinillaFInsulin-likegrowth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience, 2006823833
  170. 170. BusiguinaSet alNeurodegeneration is associated to changes in serum insulin-like growth factors. Neurobiol Dis, 2000Pt B): 657665
  171. 171. Perez-martinMand T. JAzcoitiaISierraAGarcia-seguraLM., An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus of adult female rat. Eur J Neurosci, 2003923930
  172. 172. IhrieR. Aand AAlvarez-buyllaLake-front property: a unique germinal niche by the lateral ventricles of the adult brain. Neuron, 2011674686
  173. 173. ArmulikAet alPericytes regulate the blood-brain barrier. Nature, 2010557561
  174. 174. BjarnegardMet alEndothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development, 200418471857
  175. 175. EngeMet alEndothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J, 200243074316
  176. 176. AndraeJRGalliniand CBetsholtzRole of platelet-derived growth factors in physiology and medicine. Genes Dev, 200812761312
  177. 177. DaiCet alPDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev, 200119131925
  178. 178. Jackson EL and G.-P.S. Garcia-Verdugo JM, Roy M, Quinones-Hinojosa A, VandenBerg S, Alvarez-Buylla A., PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron, 2006. 51(2): p. 187-199.
  179. 179. GensburgerCLabourdetteGand SensenbrennerMBrain basic fibroblast growth factor stimulates the proliferation of rat neuronal precursor cells in vitro. FEBS Lett, 198715
  180. 180. RichardsL. Jand B. PKilpatrickTJ, De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci U S A., 199285918595
  181. 181. JoheK. Kand M. THazelT. GDugich-djordjevicM. MMckayRD., Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev, 199631293140
  182. 182. BroudyV. Cet alHuman umbilical vein endothelial cells display high-affinity c-kit receptors and produce a soluble form of the c-kit receptor. Blood, 199421452152
  183. 183. AshmanL. KThe biology of stem cell factor and its receptor C-kit. In J Biochem Cell Biol, 1999103710351
  184. 184. JinKand S. YMaoX. OXieLGreenbergDA., Stem cell factor stimulates neurogenesis in vitro and in vivo. J Clin Invest, 2002311319
  185. 185. ErlandssonAand F. -N. KLarssonJ, Stem cell factor is a chemoattractant and a survival factor for CNS stem cells. Exp Cell Res, 2004201210
  186. 186. SunYet alVascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: evidence from knockout mice and growth factor administration. Dev Biol, 2006329335
  187. 187. AparicioSet alExpression of angiogenesis factors in human umbilical vein endothelial cells and their regulation by PEDF. Biochem Biophys Res Commun, 2005387394
  188. 188. KozakiKet alIsolation, purification, and characterization of a collagen-associated serpin, caspin, produced by murine colon adenocarcinoma cells. J Biol Chem, 19981512515130
  189. 189. MeyerCLNotariand S. PBecerraMapping the type I collagen-binding site on pigment epithelium-derived factor. Implications for its antiangiogenic activity. J Biol Chem, 20024540045407
  190. 190. SugitaYand C. GBecerraS. PSchwartzJP., Pigment epithelium-derived factor (PEDF) has direct effects on the metabolism and proliferation of microglia and indirect effects on astrocytes. J Neurosci Res, 1997710718
  191. 191. PignoloR. Jand R. MFrancisM. KCristofaloVJ., Putative role for EPC-1/PEDF in the G0 growth arrest of human diploid fibroblasts. J Cell Physiol, 20031220
  192. 192. PumigliaKand T. SPedfbridging neurovascular interactions in the stem cell niche. Nat Neurosci, 2006299300
  193. 193. AblesJ. Let alNot(ch) just development: Notch signalling in the adult brain. Nat Rev Neurosci, 2011269283
  194. 194. Ramirez-castillejoCet alPigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat Neurosci, 2006331339
  195. 195. Andreu-agulloCet alVascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone. Nat Neurosci, 200915141523
  196. 196. ParkCet alInhibition of neuronal nitric oxide synthase enhances cell proliferation in the dentate gyrus of the adrenalectomized rat. Neurosci Lett, 2001912
  197. 197. Moreno-lopezBet alNitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb. J Neurosci, 20048595
  198. 198. Murillo-carreteroMet alS-Nitrosylation of the epidermal growth factor receptor: a regulatory mechanism of receptor tyrosine kinase activity. Free Radic Biol Med, 2009471479
  199. 199. TorroglosaAet alNitric oxide decreases subventricular zone stem cell proliferation by inhibition of epidermal growth factor receptor and phosphoinositide-3-kinase/Akt pathway. Stem Cells, 20078897
  200. 200. CarreiraB. Pet alNitric oxide stimulates the proliferation of neural stem cells bypassing the epidermal growth factor receptor. Stem Cells, 201012191230
  201. 201. LiQet alModeling the neurovascular niche: VEGF- and BDNF-mediated cross-talk between neural stem cells and endothelial cells: an in vitro study. J Neurosci Res, 200616561668
  202. 202. ChenJet alEndothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci, 200523662375
  203. 203. KereverAand V. DSchnackJIchikawaNMoonCArikawa-hirasawaEEfirdJ. TMercierF., Novel extracellular matrix structures in the neural stem cell niche capture the neurogenic factor fibroblast growth factor 2 from the extracellular milieu. Stem cells, 200721462157
  204. 204. MercierFand H. GKitasakoJ. TFractonesand other basal laminae in the hypothalamus. J Comp Neurol, 2003324340
  205. 205. MercierFand H. GKitasakoJT, Anatomy of the brain neurogenic zones revisited: fractones and the fibroblast/macrophage network. J Comp Neurol, 2002170188
  206. 206. TsangK. Yand C. DCheungM. CCheahKS., The developmental roles of the extracellular matrix: beyond structure to regulation. Cell Tissue Res, 201093110
  207. 207. TsangK. Yand C. DCheungM. CCheahKS., The developmental roles of the extracellular matrix: beyond structure to regulation. Cell Tisue Res, 201093110
  208. 208. LeoneD. Pet alRegulation of neural progenitor proliferation and survival by beta1 integrins. J Cell Sci, 2005Pt 12): 25892599
  209. 209. EmsleyJ. Gand THaggalpha6beta1 integrin directs migration of neuronal precursors in adult mouse forebrain. Exp Neurol, 2003273285
  210. 210. AliS. APappasI. Sand ParnavelasJ. GCollagen type IV promotes the differentiation of neuronal progenitors and inhibits astroglial differentiation in cortical cell cultures. Brain Res Dev Brain Res, 19983138
  211. 211. BrücknerGet alRegion and lamina-specific distribution of extracellular matrix proteoglycans, hyaluronan and tenascin-R in the mouse hippocampal formation. J Chem Nauroanat, 20033750
  212. 212. GatesM. Aet alCell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres. J Comp Neurol, 1995249266
  213. 213. SeghezziGand R. CPatelSGualandrisAPintucciGRobbinsE. SShapiroR. LGallowayA. CRifkinD. BMignattiP., Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol, 199816591673
  214. 214. BiroSet alExpression and subcellular distribution of basic fibroblast growth factor are regulated during migration of endothelial cells. Circ Res, 1994485494
  215. 215. KilpatrickT. Jand B. PF., Cloned multipotential precursors from the mouse cerebrum require FGF-2, whereas glial restricted precursors are stimulated with either FGF-2 or EGF. J Neurosci, 1995Pt 1): 36533651
  216. 216. GrittiAand C. LParatiE. AFrolichsthalPGalliRWankeEFaravelliLMorassuttiD. JRoisenFNickelD. DVescoviAL., Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci, 199610911100
  217. 217. PalmerT. Dand G. FTakahashiJ, The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci, 1997389404
  218. 218. CiccoliniFand S. CN., Fibroblast growth factor 2 (FGF-2) promotes acquisition of epidermal growth factor (EGF) responsiveness in mouse striatal precursor cells: identification of neural precursors responding to both EGF and FGF-2. J Neurosci, 199878697880
  219. 219. DoetschFand C. IPetreanuLGarcia-verdugoJ. MAlvarez-buyllaA., EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron, 200210211034
  220. 220. VaccarinoF. Mand R. RSchwartzM. LNilsenJRheeJZhouMDoetschmanTCoffinJ. DWylandJ. JHungYT., Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis Nat Neurosci, 1999848
  221. 221. RaballoRand L. -C. RRheeJLeckmanJ. FSchwartzM. LVaccarinoFM., Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex. J Neurosci, 200050125023
  222. 222. AlzheimerCand WernerSFibroblast growth factors and neuroprotection. Adv Exp Med Biol, 200233353351
  223. 223. ZhengWR. SNowakowskiand F. MVaccarinoFibroblast growth factor 2 is required for maintaining the neural stem cell pool in the mouse brain subventricular zone. Dev Neurosci, 2004181196
  224. 224. NeivaK. Gand M. MZhangZWarnerK. AKarlENörJE., Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. Neoplasia, 2009583593
  225. 225. Gomez-gaviroM. Vet alThe Vascular Stem Cell Niche. J Cardiovasc Transl Res, 2012
  226. 226. KokovayEet alAdult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling. Cell Stem Cell, 2010163173
  227. 227. AguirreAM. ERubioand VGalloNotch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature, 2010323327
  228. 228. MathieuCand F. PSii-feliceKEtienneOHatonCMabondzoABoussinF. DMouthonMA., Endothelial cell-derived bone morphogenetic proteins control proliferation of neural stem/progenitor cells. Mol Cell Neurosci, 2008569577
  229. 229. LimD. Aand T. JTramontinA. DHerreraD. GGarcía-verdugoJ. MAlvarez-buyllaA., Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron, 2000713726
  230. 230. GrossR. Eand M. PMehlerM. FZangZSantschiLKesslerJA., Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron, 1996595606
  231. 231. ChenH. Land P. DM., Concise review: bone morphogenetic protein pleiotropism in neural stem cells and their derivatives--alternative pathways, convergent signals. Stem Cells, 20076368
  232. 232. BauerSand PattersonP. HLeukemia inhibitory factor promotes neural stem cell self-renewal in the adult brain. J Neurosci, 20061208912099
  233. 233. YingQ. Land C. INicholsJSmithA., BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell, 2003281292
  234. 234. HillW. Dand M. -S. AHessD. CCarothersJ. JZhengJHaleDMaedaMFaganS. CCarrollJ. EConwayS. JSdf-1CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol, 20048496
  235. 235. ImitolaJand P. KRaddassiKMuellerF. JNietoMTengY. DFrenkelDLiJSidmanR. LWalshC. ASnyderE. YKhourySJ., Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A., 20041811718122
  236. 236. TranP. Band V. TRenDMillerRJ., Chemokine receptors are expressed widely by embryonic and adult neural progenitor cells. J neurosci Res, 20042034
  237. 237. RobinA. Mand W. LZhangZ. GZhangR. LKatakowskiMZhangLWangYZhangCChoppM., Stromal cell-derived factor 1alpha mediates neural progenitor cell motility after focal cerebral ischemia. J Cereb Blood Flow Metab, 2006125134
  238. 238. ThoredPand C. EArvidssonAAhleniusHKallurTDarsaliaVEkdahlC. TKokaiaZLindvallO., Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells, 2006739747
  239. 239. KallmannB. Aand H. VWagnerSButtmannMBayasATonnJ. CRieckmannP., Characteristic gene expression profile of primary human cerebral endothelial cells. FASEB J, 2002589591
  240. 240. CarmelietPand T.-L. M., Common mechanisms of nerve and blood vessel wiring. Nature, 2005193200
  241. 241. WardN. Land L. JC., The neurovascular unit and its growth factors: coordinated response in the vascular and nervous systems. Neurol Res, 2004870883
  242. 242. JonesNand D. DIljinKAlitaloK., Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol, 2001257267
  243. 243. StummR. Kand J. VRummelJCulmseeCPfeifferMKrieglsteinJHölltVSchulzS., A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci, 200258655878
  244. 244. AraiFet alTie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell, 2004149161
  245. 245. KoochekpourSand P. GMerzakA, ascular endothelial growth factor production is stimulated by gangliosides and TGF-beta isoforms in human glioma cells in vitro. Cancer Lett, 1996209215
  246. 246. BreierGet alTransforming growth factor-beta and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis. Int J Cancer, 2002142148
  247. 247. HirschiK. Kand B. NLaiLDeanD. ASchwartzR. JZimmerWE., Transforming growth factor-beta induction of smooth muscle cell phenotpye requires transcriptional and post-transcriptional control of serum response factor. J Biol Chem., 200262876295
  248. 248. Antonelli-orlidgeAet alAn activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes. Proc Natl Acad Sci U S A., 198945444548
  249. 249. SatoYand L. RTsuboiRMosesHRifkinDB., Characterization of the activation of latent TGF-beta by co-cultures of endothelial cells and pericytes or smooth muscle cells: a self-regulating system. J Cell Biol, 1990757763
  250. 250. BrionneT. Cet alLoss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron, 200311331145
  251. 251. BuckwalterM. Set alChronically increased transforming growth factor-beta1 strongly inhibits hippocampal neurogenesis in aged mice. Am J Pathol, 2006154164
  252. 252. WachsF. Pet alTransforming growth factor-beta1 is a negative modulator of adult neurogenesis. J Neuropathol Exp Neurol, 2006358370
  253. 253. AdamsR. Hand KleinREph receptors and ephrin ligands. essential mediators of vascular development. Trends Cardiovas Med, 2000183188
  254. 254. HolmbergJand S. KArmulikAEdoffKSpaldingKMommaSCassidyRFlanaganJ. GFrisénJEphrin-areverse signaling negatively regulates neural progenitor proliferation and neurogenesis. Genes Dev, 2005462471
  255. 255. ConoverJ. Cand G. -V. JDoetschFGaleN. WYancopoulosG. DAlvarez-buyllaA., Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone. Nat Neurosci, 200010911097
  256. 256. GaleN. Wand P. LBalukPKwanMHolashJDechiaraT. MMcdonaldD. MYancopoulosG. DEphrin-bselectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev Biol, 2001151160
  257. 257. Alvarez-buyllaAand LimD. AFor the long run: maintaining germinal niches in the adult brain. Neuron, 2004683686
  258. 258. NomuraTet alEphB signaling controls lineage plasticity of adult neural stem cell niche cells. Cell Stem Cell, 2010730743
  259. 259. ShingoTand E. EGreggCFujikawaHHassamRGearyCCrossJ. CWeissSPregnancy-stimulatedneurogenesis in the adult female forebrain mediated by prolactin. Science, 2003117120
  260. 260. AbrousD. NKoehlMand Le Moal M, Adult neurogenesis: from precursors to network and physiology. Physiol Rev., 2005523569
  261. 261. MasudaSand S. RChikumaMInsulin-likegrowth factors and insulin stimulate erythropoietin production in primary cultured astrocytes. Brain Res, 19976370
  262. 262. JohnsLand D. JSinclairA. JHypoxiahypoglycemia-induced amino acid release is decreased in vitro by preconditioning. Biochem Biophys Res Commun, 2000134136
  263. 263. BlondeauNet alK(ATP) channel openers, adenosine agonists and epileptic preconditioning are stress signals inducing hippocampal neuroprotection. Neuroscience, 2000465474
  264. 264. BrinesM. Let alErythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A., 20001052610531
  265. 265. EidTand C. ABrinesM. LSpencerD. DKimJ. HSchweitzerJ. SOttersenO. PDe LanerolleNC., Increased expression of erythropoietin receptor on blood vessels in the human epileptogenic hippocampus with sclerosis. J Neuropathol Exp Neurol, 20047383
  266. 266. HassounaIet alErythropoietin augments survival of glioma cells after radiation and temozolomide. Int J Radiat Oncol Biol Phys, 2008927934
  267. 267. RuscherKand K. MFreyerDIsaevNMegowDSawitzkiBPrillerJDirnaglUMeiselA., Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci, 20021029110301
  268. 268. CalabreseCet alA perivascular niche for brain tumor stem cells. Cancer Cell, 20076982

Written By

Joshua S. Goldberg and Karen K. Hirschi

Published: 24 April 2013