Immortalized endothelial cell lines for in vitro blood–brain barrier models: A systematic review

Rahman, Nurul Adhwa; Rasil, Alifah Nur’ain Haji Mat; Meyding‐Lamadé, Uta; Craemer, Eva Maria; Diah, Suwarni; Tuah, Ani Afiqah; Muharram, Siti Hanna

doi:10.1016/j.brainres.2016.04.024

Cited by 73 publications

(62 citation statements)

References 183 publications

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“…Once confluent, TEER values up to 38.20 Ωcm 2 were recorded, in line with values reported by others using this cell line [36, 37]. Inflammatory conditions were mimicked by stimulation with TNF- α and/or IFN- γ , two cytokines known to activate endothelial cells [38] and to be critically involved in the pathogenesis of several neuroinflammatory diseases [39–45].…”

Section: Discussionsupporting

confidence: 82%

Increased Transendothelial Transport of CCL3 Is Insufficient to Drive Immune Cell Transmigration through the Blood–Brain Barrier under Inflammatory Conditions In Vitro

Laere

Sousa

Meena

et al. 2017

Mediators of Inflammation

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Many neuroinflammatory diseases are characterized by massive immune cell infiltration into the central nervous system. Identifying the underlying mechanisms could aid in the development of therapeutic strategies specifically interfering with inflammatory cell trafficking. To achieve this, we implemented and validated a blood–brain barrier (BBB) model to study chemokine secretion, chemokine transport, and leukocyte trafficking in vitro. In a coculture model consisting of a human cerebral microvascular endothelial cell line and human astrocytes, proinflammatory stimulation downregulated the expression of tight junction proteins, while the expression of adhesion molecules and chemokines was upregulated. Moreover, chemokine transport across BBB cocultures was upregulated, as evidenced by a significantly increased concentration of the inflammatory chemokine CCL3 at the luminal side following proinflammatory stimulation. CCL3 transport occurred independently of the chemokine receptors CCR1 and CCR5, albeit that migrated cells displayed increased expression of CCR1 and CCR5. However, overall leukocyte transmigration was reduced in inflammatory conditions, although higher numbers of leukocytes adhered to activated endothelial cells. Altogether, our findings demonstrate that prominent barrier activation following proinflammatory stimulation is insufficient to drive immune cell recruitment, suggesting that additional traffic cues are crucial to mediate the increased immune cell infiltration seen in vivo during neuroinflammation.

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Section: Discussionsupporting

confidence: 82%

Increased Transendothelial Transport of CCL3 Is Insufficient to Drive Immune Cell Transmigration through the Blood–Brain Barrier under Inflammatory Conditions In Vitro

Laere

Sousa

Meena

et al. 2017

Mediators of Inflammation

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“…Therefore, we adopted a two-step seeding protocol as described by Herland and coworkers 50 to restrict permeability to paracellular tracers, express functional P-Glycoprotein (P-gp) and other efflux transporters (e.g., ATP-binding cassette transporters), undergo receptor-mediated transport, respond to inflammatory cytokines and flow-based shear stresses, form vasculature with an inner lumen, and express tight junction proteins (e.g., JAM-A, Claudin-5, ZO-1), similar to in vivo human BBB. [55][56][57][58][59] Thus, hCMEC/D3 exhibits the desired BBB characteristics to be used for a model of the BBB.…”

Section: Culture Of Hcmec/d3 Cells In μHub Devicementioning

confidence: 99%

A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

Brown

Nowak

Bayles

et al. 2019

Bioengineering & Transla Med

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Microfluidic cellular models, commonly referred to as “organs‐on‐chips,” continue to advance the field of bioengineering via the development of accurate and higher throughput models, captivating the essence of living human organs. This class of models can mimic key in vivo features, including shear stresses and cellular architectures, in ways that cannot be realized by traditional two‐dimensional in vitro models. Despite such progress, current organ‐on‐a‐chip models are often overly complex, require highly specialized setups and equipment, and lack the ability to easily ascertain temporal and spatial differences in the transport kinetics of compounds translocating across cellular barriers. To address this challenge, we report the development of a three‐dimensional human blood brain barrier (BBB) microfluidic model (μHuB) using human cerebral microvascular endothelial cells (hCMEC/D3) and primary human astrocytes within a commercially available microfluidic platform. Within μHuB, hCMEC/D3 monolayers withstood physiologically relevant shear stresses (2.73 dyn/cm 2 ) over a period of 24 hr and formed a complete inner lumen, resembling in vivo blood capillaries. Monolayers within μHuB expressed phenotypical tight junction markers (Claudin‐5 and ZO‐1), which increased expression after the presence of hemodynamic‐like shear stress. Negligible cell injury was observed when the monolayers were cultured statically, conditioned to shear stress, and subjected to nonfluorescent dextran (70 kDa) transport studies. μHuB experienced size‐selective permeability of 10 and 70 kDa dextrans similar to other BBB models. However, with the ability to probe temporal and spatial evolution of solute distribution, μHuBs possess the ability to capture the true variability in permeability across a cellular monolayer over time and allow for evaluation of the full breadth of permeabilities that would otherwise be lost using traditional end‐point sampling techniques. Overall, the μHuB platform provides a simplified, easy‐to‐use model to further investigate the complexities of the human BBB in real‐time and can be readily adapted to incorporate additional cell types of the neurovascular unit and beyond.

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“…Recently, Rahman et al, in a systematic narrative review, listed a total of 36 immortalized endothelial cell lines being used in BBB modeling. The authors ranked human brain microvascular endothelial cell line hCMEC/D3, rat endothelial cell line RBE4 and mouse brain microvascular endothelial cell line bEnd.3 as the top three based on the frequency of their use [22]. The more frequent use of a human-derived brain microvascular cell line is rationalized by the fact that it represents a more realistic match of the human NVU.…”

Section: Cell Culture-based In Vitro Bbb Models: Static Systemsmentioning

confidence: 99%

New experimental models of the blood-brain barrier for CNS drug discovery

Kaisar

Sajja

Prasad

et al. 2016

Expert Opinion on Drug Discovery

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108

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Introduction The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases. Area covered This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms. Expert opinion Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms.

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Immortalized endothelial cell lines for in vitro blood–brain barrier models: A systematic review

Cited by 73 publications

References 183 publications

Increased Transendothelial Transport of CCL3 Is Insufficient to Drive Immune Cell Transmigration through the Blood–Brain Barrier under Inflammatory Conditions In Vitro

Increased Transendothelial Transport of CCL3 Is Insufficient to Drive Immune Cell Transmigration through the Blood–Brain Barrier under Inflammatory Conditions In Vitro

A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

New experimental models of the blood-brain barrier for CNS drug discovery

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