Stroke and Drug Delivery— In Vitro Models of the Ischemic Blood-Brain Barrier

Tornabene, Erica; Brodin, Birger

doi:10.1016/j.xphs.2015.11.041

Cited by 23 publications

(18 citation statements)

References 83 publications

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“…As such, this model stands as a first-line benchmark for screening molecules targeting MBL. On the other hand, primary cells are more closely related to the physiology of endothelial cells, better mirroring the in vivo properties of the barrier, 21 and therefore should be used to run the final validation experiment. Having reproduced MBL deposition after in vitro ischemia with both cell types, we found our model suitable for thorough drug screening before moving on to animal models, in line with ethical use of in vivo research.…”

Section: And Inmentioning

confidence: 99%

Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells

Neglia

Fumagalli

Orsini

et al. 2019

J Cereb Blood Flow Metab

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Mannose-binding lectin (MBL), an initiator of the lectin pathway, is detrimental in ischemic stroke. MBL deposition on the ischemic endothelium indicates the beginning of its actions, but downstream mechanisms are not clear yet. We investigated MBL interactions with the ischemic endothelium by exposing human brain microvascular endothelial cells (hBMECs) to protocols of ischemia. Cells were exposed to hypoxia or oxygen–glucose deprivation (OGD), and re-oxygenated with human serum (HS) or recombinant MBL (rhMBL). Hypoxic hBMECs re-oxygenated with HS showed increased complement system activation (C3c deposition, +59%) and MBL deposition (+93%) than normoxic cells. Super-resolution microscopy showed MBL internalization in hypoxic cells and altered cytoskeletal organization, indicating a potential MBL action on the endothelial structure. To isolate MBL effect, hBMECs were re-oxygenated with rhMBL after hypoxia/OGD. In both conditions, MBL reduced viability (hypoxia: −25%, OGD: −34%) compared to conditions without MBL, showing a direct toxic effect. Ischemic cells also showed greater MBL deposition (hypoxia: +143%, OGD: +126%) than normoxic cells. These results were confirmed with primary hBMECs exposed to OGD (increased MBL-induced cell death: +226%, and MBL deposition: +104%). The present findings demonstrate that MBL can exert a direct deleterious effect on ischemic brain endothelial cells in vitro, independently from complement activation.

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Section: And Inmentioning

confidence: 99%

Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells

Neglia

Fumagalli

Orsini

et al. 2019

J Cereb Blood Flow Metab

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“…The OGD technique, applied to cultures of pure primary neurons or mixed cultures of glia and neurons, is the most commonly used in vitro model of stroke (Tornabene and Brodin, 2016). Depriving cultured neurons of oxygen and glucose supplies simulates, to a certain extent, in vivo ischemic conditions.…”

Section: In Vitro and Animal Models For The Study Of Ischemic Strokementioning

confidence: 99%

Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke

Wei

Jiang

et al. 2017

Progress in Neurobiology

127

117

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One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke.

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“…It is known that the bloodbrain barrier can be damaged by hypoxia, e.g. after an ischemic stroke [35][36][37] . To simulate this process, we have subjected brain spheroids to 24 h of hypoxia, followed by 30 min incubation with nanoparticles.…”

mentioning

confidence: 99%

Transport of ultrasmall gold nanoparticles (2 nm) across the blood–brain barrier in a six-cell brain spheroid model

Sokolova

Mekky

Meer

et al. 2020

Sci Rep

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The blood–brain barrier (BBB) is an efficient barrier for molecules and drugs. Multicellular 3D spheroids display reproducible BBB features and functions. The spheroids used here were composed of six brain cell types: Astrocytes, pericytes, endothelial cells, microglia cells, oligodendrocytes, and neurons. They form an in vitro BBB that regulates the transport of compounds into the spheroid. The penetration of fluorescent ultrasmall gold nanoparticles (core diameter 2 nm; hydrodynamic diameter 3–4 nm) across the BBB was studied as a function of time by confocal laser scanning microscopy, with the dissolved fluorescent dye (FAM-alkyne) as a control. The nanoparticles readily entered the interior of the spheroid, whereas the dissolved dye alone did not penetrate the BBB. We present a model that is based on a time-dependent opening of the BBB for nanoparticles, followed by a rapid diffusion into the center of the spheroid. After the spheroids underwent hypoxia (0.1% O2; 24 h), the BBB was more permeable, permitting the uptake of more nanoparticles and also of dissolved dye molecules. Together with our previous observations that such nanoparticles can easily enter cells and even the cell nucleus, these data provide evidence that ultrasmall nanoparticle can cross the blood brain barrier.

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Stroke and Drug Delivery— In Vitro Models of the Ischemic Blood-Brain Barrier

Cited by 23 publications

References 83 publications

Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells

Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells

Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke

Transport of ultrasmall gold nanoparticles (2 nm) across the blood–brain barrier in a six-cell brain spheroid model

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