Stepwise impairment of neural stem cell proliferation and neurogenesis concomitant with disruption of blood-brain barrier in recurrent ischemic stroke

Lin, Ruihe; Lang, Michael J; Heinsinger, Nicolette M.; Stricsek, Geoffrey; Zhang, Justine; Iozzo, Renato V.; Rosenwasser, Robert H.; Iacovitti, Lorraine

doi:10.1016/j.nbd.2018.03.013

Cited by 18 publications

(11 citation statements)

References 61 publications

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“…Interestingly, numbers of new NPCs and neuroblasts in the contralesional SVZ were also increased. This result is consistent with previous studies 26 – 28 , and further demonstrates the intrinsic connectivity between bilateral brain regions. Furthermore, it was supposed that the effects of DBS therapy on neurogenesis may rely on the mobilization stimulus of cortical ischemia.…”

Section: Discussionsupporting

confidence: 93%

Electrical stimulation of the lateral cerebellar nucleus promotes neurogenesis in rats after motor cortical ischemia

Sun

et al. 2020

Sci Rep

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Deep brain stimulation (DBS) has been tentatively explored to promote motor recovery after stroke. Stroke could transiently activate endogenous self-repair processes, including neurogenesis in the subventricular zone (SVZ). In this regard, it is of considerable clinical interest to study whether DBS of the lateral cerebellar nucleus (LCN) could promote neurogenesis in the SVZ for functional recovery after stroke. In the present study, rats were trained on the pasta matrix reaching task and the ladder rung walking task before surgery. And then an electrode was implanted in the LCN following cortical ischemia induced by endothelin-1 injection. After 1 week of recovery, LCN DBS coupled with motor training for two weeks promoted motor function recovery, and reduced the infarct volumes post-ischemia. LCN DBS augmented poststroke neurogenetic responses, characterized by proliferation of neural progenitor cells (NPCs) and neuroblasts in the SVZ and subsequent differentiation into neurons in the ischemic penumbra at 21 days poststroke. DBS with the same stimulus parameters at 1 month after ischemia could also increase nascent neuroblasts in the SVZ and newly matured neurons in the perilesional cortex at 42 days poststroke. These results suggest that LCN DBS promotes endogenous neurogenesis for neurorestoration after cortical ischemia.

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Section: Discussionsupporting

confidence: 93%

Electrical stimulation of the lateral cerebellar nucleus promotes neurogenesis in rats after motor cortical ischemia

Sun

et al. 2020

Sci Rep

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“…Similarly, our previous studies showed that the BBB in all stem cell niches also becomes more porous after stroke . As infarction does not cause direct damage to niches, particularly SGZ in MCAO model which is far from the infarct, this effect is likely mediated by circulating factors leaking through the BBB . That cells of the SGZ niche are capable of responding to circulating factors is further suggested by the presence of fine NSC processes which ensheath local vessels .…”

Section: Discussionmentioning

confidence: 53%

“…In contrast, the SGZ does not respond to infused VEGF 165 with enhanced neurogenesis, likely as a result of its impermeable BBB. However, after stroke, our previous studies show that even the BBB in SGZ which is not directly damaged by MCAO becomes leaky to circulating factors and induces stem cell proliferation and differentiation . Together, these results suggest that amplified systemic VEGF is capable of driving stem cell activities in niches lacking a complete BBB in a fashion analogous to stroke where NSCs access to increased circulating levels of VEGF through a compromised BBB impacts neurogenesis.…”

Section: Discussionmentioning

confidence: 84%

“…In our earlier studies, this enhanced leakiness has been positively correlated with increased stem cell proliferation and neurogenesis in the SVZ and CVOs after stroke . More recently, we showed that even the SGZ whose BBB is not porous in the normal brain becomes leaky after MCAO . The heightened permeability in brain niches may increase niche access to systemic factors especially after stroke and/or facilitate greater contact between NSCs and cells of the BBB (i.e., ECs, pericytes, and astrocytes), all of which could be potentially important for signaling stem cell activities.…”

Section: Introductionmentioning

confidence: 75%

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Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain

et al. 2018

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It is well documented that adult neural stem cells (NSCs) residing in the subventricular zone (SVZ) and the subgranular zone (SGZ) are induced to proliferate and differentiate into new neurons after injury such as stroke and hypoxia. However, the role of injury-related cues in driving this process and the means by which they communicate with NSCs remains largely unknown. Recently, the coupling of neurogenesis and angiogenesis and the extensive close contact between vascular cells and other niche cells, known as the neurovascular unit (NVU), has attracted interest. Further facilitating communication between blood and NSCs is a permeable blood-brain-barrier (BBB) present in most niches, making vascular cells a potential conduit between systemic signals, such as vascular endothelial growth factor (VEGF), and NSCs in the niche, which could play an important role in regulating neurogenesis. We show that the leaky BBB in stem cell niches of the intact and stroke brain can respond to circulating VEGF 165 to drive induction of the Notch ligand DLL4 (one of the most important cues in angiogenesis) in endothelial cells (ECs), pericytes, and further induce significant proliferation and neurogenesis of stem cells. STEM CELLS 2019;37:395-406 SIGNIFICANCE STATEMENTThe leaky blood-brain barrier in niches of the intact and stroke brain can respond to circulating VEGF 165 to drive neural stem cells (NSCs) activation and neurogenesis. Vascular endothelial growth factor (VEGF 165 ) induces expression of the Notch ligand DLL4 in endothelial cells, pericytes, after stroke or oxygen-glucose deprivation. The enhanced DLL4-Notch signaling and crosstalk between vasculature cells and NSCs regulate the activities of NSCs when triggered by systemic stroke-induced factors. Animals were divided into seven different groups according to the experiments. For more details, please see Supporting Information Material and Methods.

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“…However, seizures and traumatic brain injuries also acutely increase neurogenesis but have negative long-term effects on function, which may be related to the fact that excitotoxic stimuli appear to activate the normally quiescent NSCs to divide (Gao et al, 2009; Lugert et al, 2010). Likewise, an ischemic brain injury, which initially induces a surge in NSC division in the subgranular zone (SGZ), ultimately leads to the long-term impairment of proliferation and neurogenesis (Lin et al, 2018). Our data suggest that a detrimental consequence of aberrantly activating quiescent NSCs is the premature exhaustion of a finite NSC pool.…”

Section: Discussionmentioning

confidence: 99%

Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

Iascone

Petrof

et al. 2019

Cell Reports

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SUMMARY Adult hippocampal neurogenesis has been reported to be decreased, increased, or not changed in Alzheimer’s disease (AD) patients and related transgenic mouse models. These disparate findings may relate to differences in disease stage, or the presence of seizures, which are associated with AD and can stimulate neurogenesis. In this study, we investigate a transgenic mouse model of AD that exhibits seizures similarly to AD patients and find that neurogenesis is increased in early stages of disease, as spontaneous seizures became evident, but is decreased below control levels as seizures recur. Treatment with the antiseizure drug levetiracetam restores neurogenesis and improves performance in a neurogenesis-associated spatial discrimination task. Our results suggest that seizures stimulate, and later accelerate the depletion of, the hippocampal neural stem cell pool. These results have implications for AD as well as any disorder accompanied by recurrent seizures, such as epilepsy.

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Stepwise impairment of neural stem cell proliferation and neurogenesis concomitant with disruption of blood-brain barrier in recurrent ischemic stroke

Cited by 18 publications

References 61 publications

Electrical stimulation of the lateral cerebellar nucleus promotes neurogenesis in rats after motor cortical ischemia

Electrical stimulation of the lateral cerebellar nucleus promotes neurogenesis in rats after motor cortical ischemia

Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain

Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

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