Blood-Brain Barrier <i>In Vitro</i> Models and Their Application in Toxicology: The Report and Recommendations of ECVAM Workshop 49<sup>,</sup>

Prieto, Pilar; Blaauboer, Bas J.; Boer, Albertus G. de; Boveri, Monica; Cecchelli, Roméo; Clemedson, Cecilia; Coecke, Sandra; Forsby, Anna; Galla, Hans‐Joachim; Garberg, Per; Greenwood, John; Price, Anna; Tähti, Hanna

doi:10.1177/026119290403200107

Cited by 47 publications

(24 citation statements)

References 67 publications

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“…Here, we report the generation of a human in vitro BBB model from ECs derived from cord blood hematopoietic stem cells that is highly reproducible and stable for at least 20 days after its derivation. This model fills all the recommendations of the ECVAM workshop no 49 on the definition on an in vitro model [24]. Due to the relatively easy access to cord blood stem cells, this model can be adopted by the research community to study molecular mechanisms at the level of brain ECs in pathologies implicating the BBB such as neurodegenerative disorders (for example, Alzheimer’s disease and multiple sclerosis), stroke and traumatic brain injury, infectious processes and inflammatory pain.…”

Section: Discussionmentioning

confidence: 92%

A Stable and Reproducible Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells

et al. 2014

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The human blood brain barrier (BBB) is a selective barrier formed by human brain endothelial cells (hBECs), which is important to ensure adequate neuronal function and protect the central nervous system (CNS) from disease. The development of human in vitro BBB models is thus of utmost importance for drug discovery programs related to CNS diseases. Here, we describe a method to generate a human BBB model using cord blood-derived hematopoietic stem cells. The cells were initially differentiated into ECs followed by the induction of BBB properties by co-culture with pericytes. The brain-like endothelial cells (BLECs) express tight junctions and transporters typically observed in brain endothelium and maintain expression of most in vivo BBB properties for at least 20 days. The model is very reproducible since it can be generated from stem cells isolated from different donors and in different laboratories, and could be used to predict CNS distribution of compounds in human. Finally, we provide evidence that Wnt/β-catenin signaling pathway mediates in part the BBB inductive properties of pericytes.

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Section: Discussionmentioning

confidence: 92%

A Stable and Reproducible Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells

et al. 2014

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“…Furthermore, the purity as well as the homogeneity of the cell cultures are not easily assured because of the presence of contaminating cells like pericytes, leading to a large variability and low reproducibility (Deli et al 2005;Plattner et al 2010). Moreover, during subsequent cultivation, loss of BBB properties occurs, including suppression of transporters, therefore only low passage cells can be used (Prieto et al 2004;Terasaki et al 2003).…”

Section: Bmec Culture Modelmentioning

confidence: 99%

Brainpeps: the blood–brain barrier peptide database

et al. 2011

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Peptides are able to cross the blood-brain barrier (BBB) through various mechanisms, opening new diagnostic and therapeutic avenues. However, their BBB transport data are scattered in the literature over different disciplines, using different methodologies reporting different influx or efflux aspects. Therefore, a comprehensive BBB peptide database (Brainpeps) was constructed to collect the BBB data available in the literature. Brainpeps currently contains BBB transport information with positive as well as negative results. The database is a useful tool to prioritize peptide choices for evaluating different BBB responses or studying quantitative structure-property (BBB behaviour) relationships of peptides. Because a multitude of methods have been used to assess the BBB behaviour of compounds, we classified these methods and their responses. Moreover, the relationships between the different BBB transport methods have been clarified and visualized.

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“…As an example, measuring the neurotoxicity of a compound in neuronal systems, without considering the possibilities for that compound to reach the central nervous system over the blood-brain barrier, may lead to erroneous conclusions (Prieto et al, 2004).…”

Section: Biokinetics In In Vitro-in Vivo Extrapolation (Ivive)mentioning

confidence: 99%

Biokinetic Modeling andin Vitro–in VivoExtrapolations

Blaauboer

2010

Journal of Toxicology and Environmental Health, Part B

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105

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The introduction of in vitro methodologies in the toxicological risk assessment process requires a number of prerequisites regarding both the toxicodynamics and the biokinetics of the compounds under study. In vitro systems will need to be relevant for measuring those structural and physiological changes that are good indicators for adverse effects. Furthermore, the dose metric found to have an effect in the in vitro system should be relevant. One element in defining the appropriate dose metric is related to the kinetic behavior of the compound in the in vitro system: binding to proteins, binding to plastic, evaporation, and the interaction between the culture medium and the cells. Ways to measure and model "in vitro biokinetics" are described. Second, the appropriate dose metric in vitro, e.g., the effective concentration, will need to be extrapolated to relevant in vivo exposure scenarios. The application of physiologically based biokinetic modelling is essential in such extrapolations. The parameters needed to build these models often can be estimated based on nonanimal data, namely chemical properties (QSARs) and in vitro experiments.

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Blood-Brain Barrier In Vitro Models and Their Application in Toxicology: The Report and Recommendations of ECVAM Workshop 49^,

Cited by 47 publications

References 67 publications

A Stable and Reproducible Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells

A Stable and Reproducible Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells

Brainpeps: the blood–brain barrier peptide database

Biokinetic Modeling andin Vitro–in VivoExtrapolations

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Blood-Brain Barrier In Vitro Models and Their Application in Toxicology: The Report and Recommendations of ECVAM Workshop 49,

Cited by 47 publications

References 67 publications

A Stable and Reproducible Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells

A Stable and Reproducible Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells

Brainpeps: the blood–brain barrier peptide database

Biokinetic Modeling andin Vitro–in VivoExtrapolations

Contact Info

Product

Resources

About

Blood-Brain Barrier In Vitro Models and Their Application in Toxicology: The Report and Recommendations of ECVAM Workshop 49^,