Abstract
Blood–brain barrier (BBB) dysfunction causing edema and hemorrhagic transformation is one of the pathophysiological characteristics of stroke. Protection of BBB integrity has shown great potential in improving stroke outcome. Here, we assessed the efficacy of exosomes extracted from healthy rat serum in protection against ischemic stroke in vivo and in vitro. Exosomes were isolated by gradient centrifugation and ultracentrifugation and exosomes were characterized by transmission electron microscopy (TEM) and nanoparticle tracking video microscope. Exosomes were applied to middle cerebral artery occlusion (MCAO) rats or brain microvascular endothelial cell line (bEnd.3) subjected to oxygen-glucose deprivation (OGD) injury. Serum-derived exosomes were injected intravenously into adult male rats 2 h after transient MCAO. Infarct volume and gross cognitive function were assessed 24 h after reperfusion. Poststroke rats treated with serum-derived exosomes exhibited significantly reduced infarct volumes and enhanced neurological function. Apoptosis was assessed via terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining and the expression of B-cell lymphoma-2 (Bcl-2), Bax, and cleaved caspase-3 24 h after injury. Our data showed that serum exosomes treatment strikingly decreased TUNEL+ cells in the striatum, enhanced the ratio of Bcl-2 to Bax, and inhibited cleaved caspase-3 production in MCAO rats and OGD/reoxygenation insulted bEnd.3 cells. Under the consistent treatment, the expression of microtubule-associated protein 1 light chain 3B-II (LC3B-II), LC3B-I, and Sequestosome-1 (SQSTM1)/p62 was detected by Western blotting. Autolysosomes were observed via TEM. We found that serum exosomes reversed the ratio of LC3B-II to LC3B-I, prevented SQSTM1/p62 degradation, autolysosome formation, and autophagic flux. Together, these results indicated that exosomes isolated from healthy serum provided neuroprotection against experimental stroke partially via inhibition of endothelial cell apoptosis and autophagy-mediated BBB breakdown. Intravenous serum-derived exosome treatment may, therefore, provide a novel clinical therapeutic strategy for ischemic stroke.
Highlights
Stroke is one of the leading causes of morbidity and mortality worldwide (Benjamin et al, 2017) and ranks the first lethal cause in China (Yang et al, 2013; Gao et al, 2018), with ischemic stroke accounting for about 87% of total occurrence (Benjamin et al, 2017)
Recent evidence indicates that autophagy is involved in claudin5, occludin, and ZO-1 degradation after ischemic stroke and we further examined whether serum exosomes preserved tight junction proteins through autophagy
Animal cells, especially mesenchymal stem cells, macrophages, and exosomes derived from parenchymal cells, have shown good therapeutic prospects
Summary
Stroke is one of the leading causes of morbidity and mortality worldwide (Benjamin et al, 2017) and ranks the first lethal cause in China (Yang et al, 2013; Gao et al, 2018), with ischemic stroke accounting for about 87% of total occurrence (Benjamin et al, 2017). One of the pathophysiological characteristics of ischemic stroke is the destruction of the blood–brain barrier (BBB), which significantly promotes the progression of vasogenic edema formation and hemorrhagic transformation (Mracsko and Veltkamp, 2014; Alluri et al, 2015; Turner and Sharp, 2016). Various reports have indicated that preventing BBB dysfunction improves functional outcome after ischemic stroke (Reeson et al, 2015; Jiang et al, 2018; Balkaya et al, 2021). Inhibition of matrix metalloproteinase-9 (MMP-9) activity contributed to delayed thrombolysis-induced hemorrhagic transformation (Chen H.S. et al, 2015; Chen et al, 2019). Studies with plasma or blood transfusion showed great potential in treating stroke by protecting BBB integrity (Ren et al, 2020; Mamtilahun et al, 2021). It is urgent to develop effective therapeutic strategies to prevent the BBB dysfunction in ischemic stroke
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