Intravenous immunoglobulin (IVIg) provides protection against endothelial cell dysfunction and death in ischemic stroke

Widiapradja, Alexander; Santro, Tomislav; Bašta, Milan; Sobey, Christopher G.; Manzanero, Silvia

doi:10.1186/2040-7378-6-7

Cited by 19 publications

(18 citation statements)

References 16 publications

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“…Endothelial cells are key components of the BBB and are essential to neovascularization and maintenance of BBB integrity, but these functions are compromised after stroke. Treatment to attenuate BBB dysfunction may help to improve neurologic outcomes and facilitate recovery (Widiapradja et al, 2014). Here, we found that GFAP + or CD31 + cells were more abundant in eGFP + cells from the CXCR4 + CD45 − BMMNC-treated group than in those from mice treated with unfractionated BMMNCs.…”

Section: Discussionmentioning

confidence: 99%

CXCR4+CD45− BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice

Wang

Liu

Lü

et al. 2015

Brain, Behavior, and Immunity

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Cell-based therapy is considered to be a promising therapeutic strategy for stroke treatment. Although unfractionated bone marrow mononuclear cells (BMMNCs) have been tried in both preclinical and clinical trials, the effective subpopulations need to be identified. In this study, we used fluorescence-activated cell sorting to harvest the CXCR4+CD45+ and CXCR4+CD45− BMMNC subpopulations from transgenic mice that express enhanced green fluorescent protein. We then allogeneically grafted unfractionated BMMNCs or a subpopulation into mice subjected to transient middle cerebral artery occlusion (tMCAO) and compared the effects on stroke outcomes. We found that CXCR4+CD45− BMMNCs, but not CXCR4+CD45+ BMMNCs, more effectively reduced infarction volume and neurologic deficits than did unfractionated BMMNCs. Brain tissue from the ischemic hemisphere of mice treated with CXCR4+CD45− BMMNCs had higher levels of vascular endothelial growth factor and lower levels of TNF-α than did tissue from mice treated with unfractionated BMMNCs. In contrast, CXCR4+CD45+ BMMNCs showed an increase in TNF-α. Additionally, CXCR4+CD45+ and CXCR4+CD45− populations exhibited more robust migration into the lesion areas and were better able to express cell-specific markers of different linages than were the unfractionated BMMNCs. Endothelial and astrocyte cell markers did not colocalize with eGFP+ cells in the brains of tMCAO mice that received CXCR4+CD45+ BMMNCs. In vitro, the CXCR4+CD45− BMMNCs expressed significantly more Oct-4 and Nanog mRNA than did the unfractionated BMMNCs. However, we did not detect gene expression of these two pluripotent markers in CXCR4+CD45+ BMMNCs. Taken together, our study shows for the first time that the CXCR4+CD45− BMMNC subpopulation is superior to unfractionated BMMNCs in ameliorating cerebral damage in a mouse model of tMCAO and could represent a new therapeutic approach for stroke treatment.

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Section: Discussionmentioning

confidence: 99%

CXCR4+CD45− BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice

Wang

Liu

Lü

et al. 2015

Brain, Behavior, and Immunity

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“…IVIg has been previously shown to attenuate the activity of complement system, the expression of adhesion molecules, the expression and activation of inflammasome components, the induction of pro-inflammatory and apoptotic gene and protein expression and the production of cytokines (Arumugam et al, 2008: Arumugam et al, 2009Fann et al, 2013;Widiapradja et al, 2014;Lok et al, 2015). Our group has previously demonstrated that IVIg treatment protects against ischemic strokeinduced brain damage and neurological deficit in a mouse model of ischemia and reperfusion Widiapradja et al, 2012) by targeting the activation of the complement cascade and inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, IVIg can directly protect neurons against ischemic conditions by targeting inappropriately activated components of the innate immune system, such as the complement system and the toll like receptors (TLRs) Lok et al, 2015), and it can also protect brain endothelial cells from death (Widiapradja et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke

Lok

Manzanero

2016

Brain Research

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“…In the present study, our objective was to characterise an in vitro OGD model using a mouse immortalised cerebral microvascular endothelial cell line, bEnd.3. This cell line has previously been used in OGD studies . However, the time of OGD (and RO) exposure used in these studies varies greatly, making it difficult to ascertain which conditions best simulate the key features of BBB disruption in vivo.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of a mouse cerebral microvascular endothelial cell line (bEnd.3) after oxygen glucose deprivation and reoxygenation

Taher

Chin

et al. 2016

Clin Exp Pharma Physio

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Studies have utilised immortalised mouse cerebral endothelial cells (bEnd.3) exposed to oxygen glucose deprivation (OGD) to study blood-brain barrier (BBB) disruption after ischaemia. However, there is a paucity of literature describing the duration of OGD (and reoxygenation [RO]) required to best simulate BBB disruption in vivo. In this study we assessed BBB disruption in bEnd.3 cells after exposure to a range of OGD periods, and also after OGD + RO. Exposure of bEnd.3 monolayers to 4, 6, 16, or 24 hours of OGD resulted in a significant increase in permeability. The hyperpermeability after 16 or 24 hours was associated with decreased expression of tight junction proteins (occludin and claudin-5). Furthermore, there was a decrease in cell viability and increased expression of the pro-apoptotic protein, cleaved caspase-3. Exposure of bEnd.3 monolayers to 1 hour OGD+ 23 hours RO exacerbated hyperpermeability relative to 1 hour OGD, which was associated with decreased expression levels of occludin and ZO-1, but no change in cell viability or caspase-3. 4 hours OGD + 23 hours RO exacerbated hyperpermeability, decreased expression levels of tight junction proteins, decreased cell viability, and increased caspase-3 expression. Thus, bEnd.3 cells exhibit hyperpermeability, a loss of tight junction proteins, and undergo cell death, after exposure to prolonged periods of OGD. Moreover, they exhibit exacerbated hyperpermeability, a loss of tight junction proteins, and increased expression of caspase-3 after OGD + RO. These findings will facilitate the use of this cell line in studies of BBB disruption and for the testing of therapeutics.

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Intravenous immunoglobulin (IVIg) provides protection against endothelial cell dysfunction and death in ischemic stroke

Cited by 19 publications

References 16 publications

CXCR4+CD45− BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice

CXCR4+CD45− BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice

Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke

Characterisation of a mouse cerebral microvascular endothelial cell line (bEnd.3) after oxygen glucose deprivation and reoxygenation

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