Tumor-Derived Extracellular Vesicles Breach the Intact Blood–Brain Barrier via Transcytosis

Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system.

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Disruption of the Blood-Brain Barrier by Extracellular Vesicles From Preeclampsia Plasma and Hypoxic Placentae: Attenuation by Magnesium Sulfate

Hypertension ◽

10.1161/hypertensionaha.121.17744 ◽

2021 ◽

Author(s):

José León ◽

Jesenia Acurio ◽

Lina Bergman ◽

Juán López ◽

Anna Karin Wikström ◽

...

Keyword(s):

Magnesium Sulfate ◽

Blood Brain Barrier ◽

Extracellular Vesicles ◽

Normal Pregnancy ◽

Brain Barrier ◽

Cell Monolayers ◽

Cerebrovascular Complications ◽

Blood Brain

Preeclampsia, a pregnancy-related endothelial disorder, is associated with both cardiovascular and cerebrovascular complications. Preeclampsia requires the presence of a placenta as part of its pathophysiology, yet the role of this organ in the cerebrovascular complications remains unclear. Research has shown that circulating small extracellular vesicles (also known as exosomes) present in preeclampsia plasma can generate endothelial dysfunction, but it is unclear whether the impairment of function of brain endothelial cells at the blood-brain barrier is secondary to plasma-derived or placental-derived exosomes. In this study, we evaluated the effect of small extracellular vesicles isolated from plasma samples of women with preeclampsia (n=12) and women with normal pregnancy (n=11) as well as from human placental explants from normotensive pregnancies (n=6) subjected to hypoxia (1% oxygen) on the integrity of the blood-brain barrier, using both in vitro and animal models. Exposure of human-derived brain endothelial cell monolayers to plasma and plasma-derived small extracellular vesicles from preeclamptic pregnancies increased the permeability and reduced the transendothelial electrical resistance. A similar outcome was observed with hypoxic placental-derived small extracellular vesicles, which also increased the permeability to Evan’s blue in the brain of C57BL6 nonpregnant mice. Cotreatment with magnesium sulfate reversed the effects elicited by plasma, plasma-derived, and hypoxic placental-derived small extracellular vesicles in the employed models. Thus, circulating small extracellular vesicles in plasma from women with preeclampsia or from hypoxic placentae disrupt the blood-brain barrier, which can be prevented using magnesium sulfate. These findings provide new insights into the pathophysiology of cerebral complications associated with preeclampsia.

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Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier

Nature Communications ◽

10.1038/ncomms7716 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 288

Author(s):

Naoomi Tominaga ◽

Nobuyoshi Kosaka ◽

Makiko Ono ◽

Takeshi Katsuda ◽

Yusuke Yoshioka ◽

...

Keyword(s):

Cancer Cells ◽

Blood Brain Barrier ◽

Extracellular Vesicles ◽

Metastatic Cancer ◽

Brain Barrier ◽

Blood Brain ◽

Metastatic Cancer Cells

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Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood–Brain Barrier

International Journal of Molecular Sciences ◽

10.3390/ijms21113851 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3851

Author(s):

Golnaz Morad ◽

Cassandra Daisy ◽

Hasan Otu ◽

Towia Libermann ◽

Simon Dillon ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Blood Brain Barrier ◽

Extracellular Vesicles ◽

Brain Barrier ◽

Matrix Remodeling ◽

Clinical Challenge ◽

Blood Brain ◽

Dismal Prognosis ◽

Breast Cancer Brain Metastasis

Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood–brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis.

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The Transport Mechanism of Extracellular Vesicles at the Blood-Brain Barrier

Current Pharmaceutical Design ◽

10.2174/1381612823666170913164738 ◽

2018 ◽

Vol 23 (40) ◽

pp. 6206-6214 ◽

Cited By ~ 65

Author(s):

Junichi Matsumoto ◽

Tessandra Stewart ◽

William A. Banks ◽

Jing Zhang

Keyword(s):

Blood Brain Barrier ◽

Extracellular Vesicles ◽

Transport Mechanism ◽

Brain Barrier ◽

Blood Brain

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Mesenchymal Stromal Cell–Derived Small Extracellular Vesicles Induce Ischemic Neuroprotection by Modulating Leukocytes and Specifically Neutrophils

Stroke ◽

10.1161/strokeaha.119.028012 ◽

2020 ◽

Vol 51 (6) ◽

pp. 1825-1834 ◽

Cited By ~ 7

Author(s):

Chen Wang ◽

Verena Börger ◽

Maryam Sardari ◽

Florian Murke ◽

Jelena Skuljec ◽

...

Keyword(s):

Blood Brain Barrier ◽

Extracellular Vesicles ◽

Peripheral Blood ◽

Focal Cerebral Ischemia ◽

Ischemic Injury ◽

Polymorphonuclear Neutrophils ◽

Brain Barrier ◽

Neurological Recovery ◽

Neurological Deficits ◽

Blood Brain

Background and Purpose— Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) were shown to induce neurological recovery after focal cerebral ischemia in rodents and to reverse postischemic lymphopenia in peripheral blood. Since peripheral blood cells, especially polymorphonuclear neutrophils (PMNs), contribute to ischemic brain injury, we analyzed brain leukocyte responses to sEVs and investigated the role of PMNs in sEV-induced neuroprotection. Methods— Male C57Bl6/j mice were exposed to transient intraluminal middle cerebral artery occlusion. After reperfusion, vehicle or sEVs prepared from conditioned media of MSCs raised from bone marrow samples of 3 randomly selected healthy human donors were intravenously administered. sEVs obtained from normoxic and hypoxic MSCs were applied. PMNs were depleted in vehicle and MSC-sEV–treated mice. Neurological deficits, ischemic injury, blood-brain barrier integrity, peripheral blood leukocyte responses, and brain leukocyte infiltration were evaluated over 72 hours. Results— sEV preparations of all 3 donors collected from normoxic MSCs significantly reduced neurological deficits. Preparations of 2 of these donors significantly decreased infarct volume and neuronal injury. sEV-induced neuroprotection was consistently associated with a decreased brain infiltration of leukocytes, namely of PMNs, monocytes/macrophages, and lymphocytes. sEVs obtained from hypoxic MSCs (1% O 2 ) had similar effects on neurological deficits and ischemic injury as MSC-sEVs obtained under regular conditions (21% O 2 ) but also reduced serum IgG extravasation—a marker of blood-brain barrier permeability. PMN depletion mimicked the effects of MSC-sEVs on neurological recovery, ischemic injury, and brain PMN, monocyte, and lymphocyte counts. Combined MSC-sEV administration and PMN depletion did not have any effects superior to PMN depletion in any of the readouts examined. Conclusions— Leukocytes and specifically PMNs contribute to MSC-sEV–induced ischemic neuroprotection. Individual MSC-sEV preparations may differ in their neuroprotective activities. Potency assays are urgently needed to identify their therapeutic efficacy before clinical application. Visual Overview— An online visual overview is available for this article.

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Plasma Extracellular Vesicles in Children with OSA Disrupt Blood–Brain Barrier Integrity and Endothelial Cell Wound Healing In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms20246233 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6233 ◽

Cited By ~ 1

Author(s):

Abdelnaby Khalyfa ◽

David Gozal ◽

Leila Kheirandish-Gozal

Keyword(s):

Wound Healing ◽

Endothelial Cell ◽

Blood Brain Barrier ◽

Extracellular Vesicles ◽

Cognitive Deficits ◽

Brain Barrier ◽

Neurocognitive Deficits ◽

Barrier Integrity ◽

Blood Brain ◽

Obstructive Sleep

Pediatric obstructive sleep apnea (P-OSA) is associated with neurocognitive deficits and endothelial dysfunction, suggesting the possibility that disruption of the blood–brain barrier (BBB) may underlie these morbidities. Extracellular vesicles (EVs), which include exosomes, are small particles involved in cell–cell communications via different mechanisms and could play a role in OSA-associated end-organ injury. To examine the roles of EVs in BBB dysfunction, we recruited three groups of children: (a) absence of OSA or cognitive deficits (CL, n = 6), (b) OSA but no evidence of cognitive deficits (OSA-NC(−), n = 12), and (c) OSA with evidence of neurocognitive deficits (OSA-NC(+), n = 12). All children were age-, gender-, ethnicity-, and BMI-z-score-matched, and those with OSA were also apnea–hypopnea index (AHI)-matched. Plasma EVs were characterized, quantified, and applied on multiple endothelial cell types (HCAEC, HIAEC, human HMVEC-D, HMVEC-C, HMVEC-L, and hCMEC/D3) while measuring monolayer barrier integrity and wound-healing responses. EVs from OSA children induced significant declines in hCMEC/D3 transendothelial impedance compared to CL (p < 0.001), and such changes were greater in NC(+) compared to NC(−) (p < 0.01). The effects of EVs from each group on wound healing for HCAEC, HIAEC, HMVED-d, and hCMEC/D3 cells were similar, but exhibited significant differences across the three groups, with evidence of disrupted wound healing in P-OSA. However, wound healing in HMVEC-C was only affected by NC(+) (p < 0.01 vs. NC(−) or controls (CO). Furthermore, no significant differences emerged in HMVEC-L cell wound healing across all three groups. We conclude that circulating plasma EVs in P-OSA disrupt the integrity of the BBB and exert adverse effects on endothelial wound healing, particularly among OSA-NC(+) children, while also exhibiting endothelial cell type selectivity. Thus, circulating EVs cargo may play important roles in the emergence of end-organ morbidity in pediatric OSA.

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