Diverse Roles of the Vasculature within the Neural Stem Cell Niche

Goldberg, Joshua S.; Hirschi, Karen K.

doi:10.2217/rme.09.61

Cited by 109 publications

(81 citation statements)

References 206 publications

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“…In principle, BVs may impact SC performance not only by virtue of providing perfusion and distributing blood-borne factors but also in a perfusion-independent manner via production of paracrinically acting "angiocrine" factors (47)(48)(49). Could enhanced neurogenesis be due simply to a quantitative increase of the niche vasculature or, alternatively, to some qualitative change associated with vascular "rejuvenation"?…”

Section: Discussionmentioning

confidence: 99%

VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

Licht

Rothe

Kreisel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal "juvenile" NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an "aged" systemic milieu.adult neurogenesis | VEGF | neurovascular | aging | neural stem cells T he reserve of neuronal stem cells (NSCs) in the hippocampal dentate gyrus (DG) continues to produce neuroblasts maturing into functional neurons after birth. Adult hippocampal neurogenesis, however, rapidly declines with age, and in the rodent brain, it is barely detected beyond 8 mo of age (1-4). Several factors, including BDNF, FGF, insulin-like growth factor, VEGF, and others, were shown to enhance the basal level of hippocampal neurogenesis (reviewed in ref. 5). However, there is no report of a factor capable of inducing sustained neurogenic enhancement lasting months after its withdrawal.It has been shown that age-related decrease in hippocampal neurogenesis is associated with progressive depletion of the finite NSC pool due to the fact that neuroblast-producing asymmetrical NSC divisions can only take place a limited number of times before their terminal differentiation to astrocytes (2). Supporting the notion of an exhaustible NSC reservoir is also a study showing that experimentally forced accelerated neurogenesis results in premature NSC depletion (6) and a study showing that experimentally induced epilepsy is associated with premature NSC exhaustion (7). Balancing this deterministic view, however, certain genetic manipulations [e.g., experimental phosphatase and tensin homolog (PTEN) deletion] were shown to increase NSC number by symmetrical divisions (8). It thus remains unclear whether there are means to enforce enhanced hippocampal neurogenesis for a long period without necessarily causing premature exhaustion of the NSC reservoir and a resultant accelerated age-related neurogenic decay.

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Section: Discussionmentioning

confidence: 99%

VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

Licht

Rothe

Kreisel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, the SIRT1 action shown here provides a potential explanation for the effect of environmental stimuli on adult hippocampal neurogenesis. Moreover, aNSCs/ aNPCs are distributed near blood vessels in the adult SVZ and SGZ (Goldberg and Hirschi, 2009), and could thus quickly respond to energy changes by sensing the oxygen and nutrient signals from the blood vessels. We showed that SIRT1 could partially mediate the effect of 2-DG-induced metabolic stress on aNSC proliferation in vitro, but the in vivo evidence of SIRT1 involvement in metabolic control of adult neurogenesis remains to be further studied.…”

Section: Metabolic Regulation Of Adult Neurogenesismentioning

confidence: 99%

SIRT1 suppresses self-renewal of adult hippocampal neural stem cells

Yao

Zhai

et al. 2014

Development

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The balance between self-renewal and differentiation of adult neural stem cells (aNSCs) is essential for the maintenance of the aNSC reservoir and the continuous supply of new neurons, but how this balance is fine-tuned in the adult brain is not fully understood. Here, we investigate the role of SIRT1, an important metabolic sensor and epigenetic repressor, in regulating adult hippocampal neurogenesis in mice. We found that there was an increase in SIRT1 expression during aNSC differentiation. In Sirt1 knockout (KO) mice, as well as in brain-specific and inducible stem cell-specific conditional KO mice, the proliferation and self-renewal rates of aNSCs in vivo were elevated. Proliferation and self-renewal rates of aNSCs and adult neural progenitor cells (aNPCs) were also elevated in neurospheres derived from Sirt1 KO mice and were suppressed by the SIRT1 agonist resveratrol in neurospheres from wild-type mice. In cultured neurospheres, 2-deoxy-D-glucose-induced metabolic stress suppressed aNSC/aNPC proliferation, and this effect was mediated in part by elevating SIRT1 activity. Microarray and biochemical analysis of neurospheres suggested an inhibitory effect of SIRT1 on Notch signaling in aNSCs/aNPCs. Inhibition of Notch signaling by a γ-secretase inhibitor also largely abolished the increased aNSC/aNPC proliferation caused by Sirt1 deletion. Together, these findings indicate that SIRT1 is an important regulator of aNSC/aNPC self-renewal and a potential mediator of the effect of metabolic changes.

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“…The intermittent absence of astrocytic and PC contact with the vessel allows for transit-amplifying NSCs to directly contact the endothelium, enabling rapid signaling, and molecular exchange between the two cells (Girouard and Iadecola, 2006). The unique SVZ microvasculature suggests that a modified BBB in this niche exists (Goldberg and Hirschi, 2009).…”

Section: Cytoarchitecturementioning

confidence: 99%

“…Type-B cells control capillary tone in the SVZ due to the contractile nature of PCs (Goldberg and Hirschi, 2009). As a result, the interactions between vascular cells and NSCs are critical to the SVZ functioning as a neurogenic network.…”

Section: Cytoarchitecturementioning

confidence: 99%

Stroke Repair via Biomimicry of the Subventricular Zone

Matta

Gonzalez

2018

Front. Mater.

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Stroke is among the leading causes of death and disability worldwide, 85% of which are ischemic. Current stroke therapies are limited by a narrow effective therapeutic time and fail to effectively complete the recovery of the damaged area. Magnetic resonance imaging of the subventricular zone (SVZ) following infarct/stroke has allowed visualization of new axonal connections and projections being formed, while new immature neurons migrate from the SVZ to the peri-infarct area. Such studies suggest that the SVZ is a primary source of regenerative cells for the repair and regeneration of stroke-damaged neurons and tissue. Therefore, the development of tissue engineered scaffolds that serve as a bioreplicative SVZ niche would support the survival of multiple cell types that reside in the SVZ. Essential to replication of the human SVZ microenvironment is the establishment of microvasculature that regulates both the healthy and stroke-injured blood-brain barrier, which is dysregulated poststroke. In order to reproduce this niche, understanding how cells interact in this environment is critical, in particular neural stem cells, endothelial cells, pericytes, ependymal cells, and microglia. Remodeling and repair of the matrix-rich SVZ niche by endogenous reparative mechanisms may then support functional recovery when enhanced by an artificial niche that supports the survival and proliferation of migrating vascular and neuronal cells. Critical considerations to mimic this area include an understanding of resident cell types, delivery method, and the use of biocompatible materials. Controlling stem cell survival, differentiation, and migration are key factors to consider when transplanting stem cells. Here, we discuss the role of the SVZ architecture and resident cells in the promotion and enhancement of endogenous repair mechanisms. We elucidate the interplay between the extracellular matrix composition and cell interactions prior to and following stroke. Finally, we review current cell and neuronal niche biomimetic materials that allow for a tissue-engineered approach in order to promote structural and functional restoration of neural circuitry. By creating an artificial mimetic SVZ, tissue engineers can strive to facilitate tissue regeneration and functional recovery.

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Diverse Roles of the Vasculature within the Neural Stem Cell Niche

Cited by 109 publications

References 206 publications

VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

SIRT1 suppresses self-renewal of adult hippocampal neural stem cells

Stroke Repair via Biomimicry of the Subventricular Zone

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