The membrane mesenchymal stem cell derived conditioned medium exerts neuroprotection against focal cerebral ischemia by targeting apoptosis

Faezi, Masoumeh; Maleki, Solmaz Nasseri; Aboutaleb, Nahid; Nikougoftar, Mahin

doi:10.1016/j.jchemneu.2018.08.004

Cited by 27 publications

(25 citation statements)

References 39 publications

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“…This may be partly due to MMP2 being associated with the reversible disruption of the BBB during the early phases of infarction, in contrast to MMP9, which is elevated in the late phase resulting in the loss of tight junctions and is therefore considered to be principally responsible for disruption of the BBB 41 , 42 . These findings are compatible with the results of our evaluation of BBB integrity via EB extravasation 43 .…”

Section: Discussionsupporting

confidence: 92%

“…Finally, we evaluated the effect of hAMSCs on apoptosis in the peri-infarct areas. Despite differences in the routes used for administration (i.e., intracerebral, intravenous) and the time points of assessment (from 24 h to 21 d after transient MCAO), several studies have indicated that neuronal apoptosis around the ischemic infarction is suppressed by the administration of amniotic stem cells 39 , 43 , 53 – 55 . Although TUNEL staining is not always a specific indicator of apoptosis 32 , when combined with typical changes in nuclear morphology, it can be utilized to distinguish the apoptotic cells from the necrotic ones.…”

Section: Discussionmentioning

confidence: 99%

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Intravenous Administration of Human Amniotic Mesenchymal Stem Cells in the Subacute Phase of Cerebral Infarction in a Mouse Model Ameliorates Neurological Disturbance by Suppressing Blood Brain Barrier Disruption and Apoptosis via Immunomodulation

et al. 2021

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Neuro-inflammation plays a key role in the pathophysiology of brain infarction. Cell therapy offers a novel therapeutic option due to its effect on immunomodulatory effects. Amniotic stem cells, in particular, show promise owing to their low immunogenicity, tumorigenicity, and easy availability from amniotic membranes discarded following birth. We have successfully isolated and expanded human amniotic mesenchymal stem cells (hAMSCs). Herein, we evaluated the therapeutic effect of hAMSCs on neurological deficits after brain infarction as well as their immunomodulatory effects in a mouse model in order to understand their mechanisms of action. One day after permanent occlusion of the middle cerebral artery (MCAO), hAMSCs were intravenously administered. RT-qPCR for TNFα, iNOS, MMP2, and MMP9, immunofluorescence staining for iNOS and CD11b/c, and a TUNEL assay were performed 8 days following MCAO. An Evans Blue assay and behavioral tests were performed 2 days and several months following MCAO, respectively. The results suggest that the neurological deficits caused by cerebral infarction are improved in dose-dependent manner by the administration of hAMSCs. The mechanism appears to be through a reduction in disruption of the blood brain barrier and apoptosis in the peri-infarct region through the suppression of pro-inflammatory cytokines and the M2-to-M1 phenotype shift.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Intravenous Administration of Human Amniotic Mesenchymal Stem Cells in the Subacute Phase of Cerebral Infarction in a Mouse Model Ameliorates Neurological Disturbance by Suppressing Blood Brain Barrier Disruption and Apoptosis via Immunomodulation

et al. 2021

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“…Extravasation of dyes and changes in transendothelial electrical resistance are often used to measure permeability of the BBB barrier in vivo and in vitro. For example, Evans blue is widely regarded as the standard measurement of BBB permeability and its extravasation has been used by numerous studies to quantify BBB breakdown in vivo [ 33 – 37 ], despite some reported limitations [ 38 – 40 ]. Transport of macromolecules larger than 5 nm, such as the 40-kDa dextran, occurs through the transcellular pathway (through the cell body regulated by the cell membrane lipid bilayer) [ 41 – 44 ] that is regulated in part by cytoskeleton proteins such as actin and is altered by TNF-α activation [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C-delta inhibition protects blood-brain barrier from sepsis-induced vascular damage

Tang

Soroush

Sun

et al. 2018

J Neuroinflammation

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BackgroundNeuroinflammation often develops in sepsis leading to activation of cerebral endothelium, increased permeability of the blood-brain barrier (BBB), and neutrophil infiltration. We have identified protein kinase C-delta (PKCδ) as a critical regulator of the inflammatory response and demonstrated that pharmacologic inhibition of PKCδ by a peptide inhibitor (PKCδ-i) protected endothelial cells, decreased sepsis-mediated neutrophil influx into the lung, and prevented tissue damage. The objective of this study was to elucidate the regulation and relative contribution of PKCδ in the control of individual steps in neuroinflammation during sepsis.MethodsThe role of PKCδ in mediating human brain microvascular endothelial (HBMVEC) permeability, junctional protein expression, and leukocyte adhesion and migration was investigated in vitro using our novel BBB on-a-chip (B3C) microfluidic assay and in vivo in a rat model of sepsis induced by cecal ligation and puncture (CLP). HBMVEC were cultured under flow in the vascular channels of B3C. Confocal imaging and staining were used to confirm tight junction and lumen formation. Confluent HBMVEC were pretreated with TNF-α (10 U/ml) for 4 h in the absence or presence of PKCδ-i (5 μM) to quantify neutrophil adhesion and migration in the B3C. Permeability was measured using a 40-kDa fluorescent dextran in vitro and Evans blue dye in vivo.ResultsDuring sepsis, PKCδ is activated in the rat brain resulting in membrane translocation, a step that is attenuated by treatment with PKCδ-i. Similarly, TNF-α-mediated activation of PKCδ and its translocation in HBMVEC are attenuated by PKCδ-i in vitro. PKCδ inhibition significantly reduced TNF-α-mediated hyperpermeability and TEER decrease in vitro in activated HBMVEC and rat brain in vivo 24 h after CLP induced sepsis. TNF-α-treated HBMVEC showed interrupted tight junction expression, whereas continuous expression of tight junction protein was observed in non-treated or PKCδ-i-treated cells. PKCδ inhibition also reduced TNF-α-mediated neutrophil adhesion and migration across HBMVEC in B3C. Interestingly, while PKCδ inhibition decreased the number of adherent neutrophils to baseline (no-treatment group), it significantly reduced the number of migrated neutrophils below the baseline, suggesting a critical role of PKCδ in regulating neutrophil transmigration.ConclusionsThe BBB on-a-chip (B3C) in vitro assay is suitable for the study of BBB function as well as screening of novel therapeutics in real-time. PKCδ activation is a key signaling event that alters the structural and functional integrity of BBB leading to vascular damage and inflammation-induced tissue damage. PKCδ-TAT peptide inhibitor has therapeutic potential for the prevention or reduction of cerebrovascular injury in sepsis-induced vascular damage.

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“…Faezi et al revealed that I.C.V. administration of human amniotic mesenchymal stem cells condition medium (HAMSC-CM) 30 minutes after reperfusion reduced infarct volume, brain edema and BBB leakage by targeting apoptosis [ 80 ]. The data from Nazarinia et al further support the above foundings.…”

Section: Effects Of Cell Therapy On Bbb Integrity After Ischemic Strokementioning

confidence: 99%

The Effects and Underlying Mechanisms of Cell Therapy on Blood-Brain Barrier Integrity After Ischemic Stroke

Gao

Song

et al. 2020

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: Ischemic stroke is one of the main causes of mortality and disability worldwide. However, the efficient therapeutic strategies are still lacking. Stem/progenitor cell-based therapy, with its vigorous advantages, has emerged as a promising tool for the treatments of ischemic stroke. The mechanisms involve new neural cells and neuronal circuitry formation, antioxidation, inflammation alleviation, angiogenesis and neurogenesis promotion. In the past decades, in-depth studies have suggested that cell therapy could promote vascular stabilization and decrease blood-brain barrier (BBB) leakage after ischemic stroke. However, the effects and underlying mechanisms on BBB integrity induced by the engrafted cells in ischemic stroke have not been reviewed yet. Herein, we will update the progress in researches of the effects of cell therapy on BBB integrity after ischemic stroke and review the underlying mechanisms. First, we will present an overview of BBB dysfunction under ischemic condition and cells engraftment for ischemic treatment. Then we will summarize and discuss the current knowledge about the effects and underlying mechanisms of cell therapy on BBB integrity after ischemic stroke. In particular, we will review the most recent studies in regard to the relationship between cell therapy and BBB in tissue plasminogen activator (t-PA)-mediated therapy and diabetic stroke.

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The membrane mesenchymal stem cell derived conditioned medium exerts neuroprotection against focal cerebral ischemia by targeting apoptosis

Cited by 27 publications

References 39 publications

Intravenous Administration of Human Amniotic Mesenchymal Stem Cells in the Subacute Phase of Cerebral Infarction in a Mouse Model Ameliorates Neurological Disturbance by Suppressing Blood Brain Barrier Disruption and Apoptosis via Immunomodulation

Intravenous Administration of Human Amniotic Mesenchymal Stem Cells in the Subacute Phase of Cerebral Infarction in a Mouse Model Ameliorates Neurological Disturbance by Suppressing Blood Brain Barrier Disruption and Apoptosis via Immunomodulation

Protein kinase C-delta inhibition protects blood-brain barrier from sepsis-induced vascular damage

The Effects and Underlying Mechanisms of Cell Therapy on Blood-Brain Barrier Integrity After Ischemic Stroke

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