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

Abstract

BackgroundActivated 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.MethodsThe 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.ResultsBMSCs 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.ConclusionsBMSCs 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 materialThe online version of this article (10.1186/s12974-019-1396-5) contains supplementary material, which is available to authorized users.

Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

“…An 18-point scoring system was used to evaluate the sensorimotor deficits. Higher scores represent milder neurological deficits [6,27].…”

“…Several lines of evidence suggest that EBI after SAH may be the leading factor contributing to unfavorable outcomes following SAH [4,5]. The evidence suggests that several pathophysiological disorders during EBI activate inflammatory cascades [6]. It is of paramount importance to develop novel neuroprotective therapies to enhance recovery in the period of EBI after SAH.…”

Recent Advances in Stem Cell Research in Subarachnoid Hemorrhage

“…Although some studies showed that stem cell transplantation at both 24 h post-SAH and 6 days post-SAH had a noticeable improvement in the neurological deficit of these animal models, rapid intervention with patients suffering from SAH is preferred. In a new study published at 2019, Liu et al delivered BM-MSCs intravenously within 1 h after induction of SAH by endovascular perforation method [58]. They showed that early BM-MSCs treatment mitigated the neurobehavioral deficits, alleviated disruption to the BBB, and attenuated neuronal injury at 24 h and 72 h post-SAH.…”

Mesenchymal stromal cell secretome as a therapeutic strategy for traumatic brain injury

“…Stem cells are progenitor cells that can be isolated from various tissue of the body. The therapeutic benefits of these cells have been reported in various neurodegenerative diseases including TBI . The different types of stem cells are embryonic stem cells (ESCs), adult stem cells, and induced pluripotent stem cells.…”

“…The therapeutic benefits of these cells have been reported in various neurodegenerative diseases including TBI. 9,[12][13][14][15] The different types of stem cells are embryonic stem cells (ESCs), adult stem cells, and induced pluripotent stem cells. Due to ethical concern on the source of ESCs, the use of adult stem cells has been made as an alternative in regenerative medicine.…”