Dataset Information

Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch.

ABSTRACT:

Background

Activated microglia-mediated neuroinflammation has been regarded as an underlying key player in the pathogenesis of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). The therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) transplantation has been demonstrated in several brain injury models and is thought to involve modulation of the inflammatory response. The present study investigated the salutary effects of BMSCs on EBI after SAH and the potential mechanism mediated by Notch1 signaling pathway inhibition.

Methods

The Sprague-Dawley rats SAH model was induced by endovascular perforation method. BMSCs (3?×?10⁶ cells) were transplanted intravenously into rats, and N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a Notch1 activation inhibitor, and Notch1 small interfering RNA (siRNA) were injected intracerebroventricularly. The effects of BMSCs on EBI were assayed by neurological score, brain water content (BWC), blood-brain barrier (BBB) permeability, magnetic resonance imaging, hematoxylin and eosin staining, and Fluoro-Jade C staining. Immunofluorescence and immunohistochemistry staining, Western blotting, and quantitative real-time polymerase chain reaction were used to analyze various proteins and transcript levels. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assay.

Results

BMSCs treatment mitigated the neurobehavioral dysfunction, BWC and BBB disruption associated with EBI after SAH, reduced ionized calcium binding adapter molecule 1 and cluster of differentiation 68 staining and interleukin (IL)-1 beta, IL-6 and tumor necrosis factor alpha expression in the left hemisphere but concurrently increased IL-10 expression. DAPT or Notch1 siRNA administration reduced Notch1 signaling pathway activation following SAH, ameliorated neurobehavioral impairments, and BBB disruption; increased BWC and neuronal degeneration; and inhibited activation of microglia and production of pro-inflammatory factors. The augmentation of Notch1 signal pathway agents and phosphorylation of nuclear factor-?B after SAH were suppressed by BMSCs but the levels of Botch were upregulated in the ipsilateral hemisphere. Botch knockdown in BMSCs abrogated the protective effects of BMSCs treatment on EBI and the suppressive effects of BMSCs on Notch1 expression.

Conclusions

BMSCs treatment alleviated neurobehavioral impairments and the inflammatory response in EBI after SAH; these effects may be attributed to Botch upregulation in brain tissue, which subsequently inhibited the Notch1 signaling pathway.

SUBMITTER: Liu W

PROVIDER: S-EPMC6334441 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch.

Liu Wenchao W Li Ran R Yin Jian J Guo Shenquan S Chen Yunchang Y Fan Haiyan H Li Gancheng G Li Zhenjun Z Li Xifeng X Zhang Xin X He Xuying X Duan Chuanzhi C

Journal of neuroinflammation 20190115 1

<h4>Background</h4>Activated microglia-mediated neuroinflammation has been regarded as an underlying key player in the pathogenesis of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). The therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) transplantation has been demonstrated in several brain injury models and is thought to involve modulation of the inflammatory response. The present study investigated the salutary effects of BMSCs on EBI after SAH and the potenti ...[more]

PMID: 30646897

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Project description:ObjectiveNumerous studies have shown that neuroinflammation and brain edema play an important role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). 2-Methoxyestradiol (2-ME) has been shown to have anti-inflammatory and anti-angiogenic effects. This study aimed to investigate the effects of 2-ME on neuroinflammation and brain edema after SAH and its underlying mechanism of action.MethodsRats were used to produce an endovascular puncture model of SAH. 2-ME or the control agent was injected intraperitoneally 1 h after SAH induction. At 24 h after surgery, the neurological score, SAH grading, brain water content, and blood-brain barrier (BBB) permeability were examined. The microglial activation level in the rat brain tissue was determined using immunofluorescence staining, whereas the cell apoptosis in the rat brain tissue was assessed using terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, the levels of Interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α were measured by enzyme linked immunosorbent assay, and the expression levels of ZO-1, occludin, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and matrix metallopeptidase (MMP)-9 in the rat brain tissue were determined using western blotting.ResultsTwenty-four hours after SAH, brain water content, BBB permeability, microglial activation, and cell apoptosis were significantly increased, whereas neurological function deteriorated significantly in rats. Treatment with 2-ME significantly decreased brain water content, BBB permeability, microglial cell activation, and cell apoptosis and improved neurological dysfunction in rats. Treatment with 2-ME reduced the expression levels of inflammatory factors (IL-1β, IL-6, and TNF-α), which were significantly elevated 24 h after SAH. Treatment with 2-ME alleviated the disruption of tight junction proteins (ZO-1 and occludin), which significantly decreased 24 h after SAH. To further determine the mechanism of this protective effect, we found that 2-ME inhibited the expression of HIF-1α, MMP-9, and VEGF, which was associated with the inflammatory response to EBI and BBB disruption after SAH.Conclusion2-ME alleviated neuroinflammation and brain edema as well as improved neurological deficits after SAH in rats. The neuroprotective effect of 2-ME on EBI after SAH in rats may be related to the inhibition of neuroinflammation and brain edema.

Project description:BACKGROUND:The therapeutic effects of adipose-derived mesenchymal stem cell (ADSC) transplantation have been demonstrated in several models of central nervous system (CNS) injury and are thought to involve the modulation of the inflammatory response. However, the exact underlying molecular mechanism is poorly understood. Activation of the Jagged1/Notch signaling pathway is thought to involve inflammatory and gliotic events in the CNS. Here, we elucidated the effect of ADSC transplantation on the inflammatory reaction after spinal cord injury (SCI) and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression. METHODS:To evaluate the therapeutic effects of ADSC treatment and the potential inhibitory effects of ADSCs on Notch signaling, mice were subjected to contusion SCI, and GFP-labeled ADSCs were injected into the lesion site immediately after the injury. Locomotor function, spinal cord tissue morphology, and the levels of Notch-related proteins and proinflammatory transcripts were compared between groups. To validate the hypothesis that the therapeutic effects of ADSCs are partly due to Notch1 signaling inhibition, a Jagged1 small interfering RNA (siRNA) was injected into the spinal cord to knock down Jagged1/Notch signaling. Neuronal staining and analyses of microglia/macrophage activation and signaling pathways were performed. RESULTS:We demonstrated that ADSCs survived in the injured spinal cord for at least 28?days without differentiating into glial or neuronal elements. ADSC treatment resulted in significant downregulation of proinflammatory mediator expression and reduced ionized calcium-binding adapter molecule 1 (IBA1) and ED-1 staining in the injured spinal cord, eventually improving functional recovery. The augmentation of the Jagged1/Notch signaling pathway after SCI was suppressed by ADSC transplantation. The inhibition of the Jagged1/Notch signaling pathway by Jagged1 siRNA resulted in decreases in SCI-induced proinflammatory cytokines and the activation of microglia and an increase in the survival of neurons. Furthermore, Jagged1 knockdown suppressed the phosphorylation of JAK/STAT3 in astrocytes following SCI. CONCLUSION:The results of this study demonstrated that the therapeutic effects of ADSCs in SCI mice were partly due to Jagged1/Notch signaling pathway inhibition and a subsequent reduction in JAK/STAT3 phosphorylation in astrocytes.

Dataset Information

Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch.

Background

Methods

Results

Conclusions

Publications

Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch.

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