Instructions from the Vascular System - Directing Neural Stem Cell Fate in Health and Disease

Schildge, Sebastian; Bohrer, Christian; Pfurr, Sabrina; Mammadzada, Könül; Schachtrup, Christian

doi:10.2174/0929867321666131227162215

Cited by 7 publications

(5 citation statements)

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“…Thus, the magnitude of BMP signaling is tightly regulated in the SVZ stem cell niche, such as by the BMP inhibitor noggin, which can be released from ependymal cells to control NSPC behavior (Lim et al , ). During CNS disease with vascular damage, extracellular environmental changes, such as the leakage of vascular system components (Schachtrup et al , ), as well as growth factor and cytokine abundance (Hampton et al , ; Schachtrup et al , ; Xiao et al , ; Logan et al , ; Schildge et al , ) are thought to modify NSPC fate. However, transcriptional changes evoked by the altered NSPC environment in CNS disease remain poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes

et al. 2015

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Adult neural stem/precursor cells (NSPCs) of the subventricular zone (SVZ) are an endogenous source for neuronal replacement in CNS disease. However, adult neurogenesis is compromised after brain injury in favor of a glial cell fate, which is mainly attributed to changes in the NSPC environment. Yet, it is unknown how this unfavorable extracellular environment translates into a transcriptional program altering NSPC differentiation. Here, we show that genetic depletion of the transcriptional regulator Id3 decreased the number of astrocytes generated from SVZ-derived adult NSPCs in the cortical lesion area after traumatic brain injury. Cortical brain injury resulted in rapid BMP-2 and Id3 up-regulation in the SVZ stem cell niche. Id3 À/À adult NSPCs failed to differentiate into BMP-2-induced astrocytes, while NSPCs deficient for the Id3-controlled transcription factor E47 readily differentiated into astrocytes in the absence of BMP-2. Mechanistically, E47 repressed the expression of several astrocyte-specific genes in adult NSPCs. These results identify Id3 as the BMP-2-induced transcriptional regulator, promoting adult NSPC differentiation into astrocytes upon CNS injury and reveal a molecular link between environmental changes and NSPC differentiation in the CNS after injury.

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Section: Introductionmentioning

confidence: 99%

The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes

et al. 2015

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“…Usually, cell biological processes are largely regulated by the tissue microenvironment . Importantly, the tissue microenvironment receives blood‐derived nutrients and O 2 from the surrounding vasculature which is necessary for maintenance of cellular homeostasis . Thus, the microvessel occlusion in hypertrophic scar will have a large impact on the fibroblast biology.…”

Section: Discussionmentioning

confidence: 99%

Severe hypoxia and malnutrition collectively contribute to scar fibroblast inhibition and cell apoptosis

Lynam

Xie

Dawson

et al. 2015

Wound Repair Regeneration

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This study aims to investigate whether severe hypoxia and malnutrition in scar tissue play key roles to induce hypertrophic scar regression. And scar‐derived fibroblasts were treated with moderate/severe hypoxia and malnutrition to model condition of proliferative and regressive scar (5%O2+5%FCS and 0.5%O2 + 0.5%FCS), and normoxia with well nutrition as control (10%O2 + 10%FCS). Our results demonstrated that severe hypoxia and malnutrition resulted in significantly reduced cell viability and collagen production, as well as HIF‐1, VEGF, TGF‐β1, and Bcl‐2 protein expression when compared with control, and cell apoptosis occurred. Therefore, the severe hypoxia and malnutrition in scar tissue contribute to fibroblast inhibition and cell apoptosis, which is correlated with scar regression.

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“…Our findings revealed that the bHLH TF E47 acts as a repressor of NSPC differentiation into astrocytes and that under pathological conditions, BMP-2-induced high Id3 expression in a subset of NSPCs captures E47 releasing its repression of astrocytespecific gene transcription and directing the SVZderived NSPCs toward the lesion area and astrocyte differentiation. We propose that the altered NSPC environment upon cortical injury is a key event in directing NSPC differentiation 53 and that rapid and robust upregulation of Id3 acts as the central player for overriding NSPC intrinsic programming resulting in NSPC differentiation into astrocytes. Cytokines of the TGF-b superfamily, which regulate the Id abundance, have been described to be elevated in lesion areas of mouse models for CNS disease and in human CNS pathologies.…”

Section: Resultsmentioning

confidence: 99%

ID(ealizing) control of adult subventricular zone neural stem/precursor cell differentiation for CNS regeneration

Bohrer

Schachtrup

2016

Neurogenesis

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The adult central nervous system (CNS) was considered a comparatively static tissue with little cell turnover. It is now well established that there is more plasticity than previously thought and that astrocytes act as neural stem/precursor cells (NSPCs) in the subventricular zone (SVZ). The discovery that these NSPCs can give rise to a limited number of new neurons, reactive astrocytes and oligodendrocytes contributing to brain repair in CNS disease, has raised hopes toward harnessing these cells for therapeutic interventions. Here, we will discuss the transcriptional control of adult NSPC differentiation into astrocytes in CNS disease focusing on the helix-loop-helix transcription factor protein family. In our recent study, we reported that elevated BMP-2 levels are translated into an increase in Id3 expression in adult NSPC subpopulations after cortical injury. Id3 then heterodimerizes with the basic helix-loop-helix transcription factor E47 and releases the E47-mediated repression of astrocyte-specific gene expression. Consequently, adult NSPCs preferentially differentiate into astrocytes. We believe that understanding the differentiation potential and the molecular underpinnings of NSPCs in the adult mammalian brain will help us to evaluate their contributions to brain repair and may lead to new concepts in treating human CNS diseases.

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Instructions from the Vascular System - Directing Neural Stem Cell Fate in Health and Disease

Cited by 7 publications

References 0 publications

The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes

The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes

Severe hypoxia and malnutrition collectively contribute to scar fibroblast inhibition and cell apoptosis

ID(ealizing) control of adult subventricular zone neural stem/precursor cell differentiation for CNS regeneration

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