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Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch
- Source :
- Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-20 (2019), Journal of Neuroinflammation
- Publication Year :
- 2019
- Publisher :
- BMC, 2019.
-
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-κB 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. Electronic supplementary material The online version of this article (10.1186/s12974-019-1396-5) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Male
Small interfering RNA
Immunology
Perforation (oil well)
Mesenchymal Stem Cell Transplantation
lcsh:RC346-429
Capillary Permeability
Rats, Sprague-Dawley
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Downregulation and upregulation
Neuroinflammation
Antigens, CD
medicine
Animals
Subarachnoid hemorrhage
RNA, Small Interfering
Receptor, Notch1
lcsh:Neurology. Diseases of the nervous system
Injections, Intraventricular
Notch1
Microglia
business.industry
General Neuroscience
Research
Mesenchymal stem cell
Intracellular Signaling Peptides and Proteins
Botch
Fluoresceins
Rats
Transplantation
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Neurology
Blood-Brain Barrier
Brain Injuries
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Cancer research
Transcription Factor HES-1
Mesenchymal stem cells
Tumor necrosis factor alpha
business
030217 neurology & neurosurgery
Signal Transduction
Early brain injury
Subjects
Details
- Language :
- English
- ISSN :
- 17422094
- Volume :
- 16
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroinflammation
- Accession number :
- edsair.doi.dedup.....1b51ab5cae7afde667160b278637fbe4