Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Moya, Elisa L.J.; Vandenhaute, Elodie; Rizzi, Eleonora; Boucau, Marie-Christine; Hachani, Johan; Maubon, Nathalie; Gosselet, Fabien; Dehouck, Marie‐Pierre

doi:10.3390/pharmaceutics13060892

Cited by 13 publications

(16 citation statements)

References 49 publications

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“…These human brain-like endothelial cells (hBLECs) also express nutrient solute carrier (SLC) transporters for glucose (GLUT1/ SLC2A1 ), amino acid L-arginine (CAT1/ SLC7A1 ), monocarboxylic acids (MCT1/ SLC16A1 ), and the receptor for transferrin (TfR1/ TFRC ), as well as ATP-binding cassette (ABC) transporters such as P-glycoprotein (MDR1/ ABCB1 ) and BCRP/ ABCG2 , which play a key role in limiting drugs’ access to the brain from the blood. We have also clarified the functionality of these efflux transporters in several studies [ 14 , 16 , 17 , 18 ]. These results allowed a good qualitative and quantitative validation of hBLECs for a human in vitro BBB model [ 14 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Targeted Absolute Proteomics for Better Characterization of an In Vitro Human Blood–Brain Barrier Model Derived from Hematopoietic Stem Cells

Dehouck

Tachikawa

Hoshi

et al. 2022

Cells

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We previously developed an in vitro model of the human blood–brain barrier (BBB) based on the use of endothelial cells derived from CD34+-hematopoietic stem cells and cultured with brain pericytes. The purpose of the present study was to provide information on the protein expression levels of the transporters, receptors, tight junction/adherence junction molecules, and transporter-associated molecules of human brain-like endothelial cells (hBLECs). The absolute protein expression levels were determined by liquid chromatography–mass spectrometry-based quantitative targeted absolute proteomics and compared with those from human brain microvessels (hBMVs). The protein levels of CD144, CD147, MRP4, Annexin A6 and caveolin-1 showed more than 3-fold abundance in hBLECs, those of MCT1, Connexin 43, TfR1, and claudin-5 showed less than 3-fold differences, and the protein levels of other drug efflux transporters and nutrient transporters were less represented in hBLECs than in hBMVs. It is noteworthy that BCRP was more expressed than MDR1 in hBLECs, as this was the case for hBMVs. These results suggest that transports mediated by MCT1, TfR1, and claudin-5-related tight junction function reflect the in vivo BBB situation. The present study provided a better characterization of hBLECs and clarified the equivalence of the transport characteristics between in vitro BBB models and in vivo BBB models using LC-MS/MS-based protein quantification.

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Section: Introductionmentioning

confidence: 99%

Quantitative Targeted Absolute Proteomics for Better Characterization of an In Vitro Human Blood–Brain Barrier Model Derived from Hematopoietic Stem Cells

Dehouck

Tachikawa

Hoshi

et al. 2022

Cells

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“…High-throughput screening (HTS) has become a fundamental tool in modern drug discovery that is often used to uncover new, effective treatments for intractable diseases ( Moya et al, 2021 ). In this study, a HTS strategy was employed to discover new drugs that could mitigate MI/RI.…”

Section: Introductionmentioning

confidence: 99%

Natural Compound Library Screening Identifies Oroxin A for the Treatment of Myocardial Ischemia/Reperfusion Injury

et al. 2022

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Myocardial ischemia/reperfusion injury (MI/RI) is a serious pathophysiological process relating to cardiovascular disease. Oroxin A (OA) is a natural flavonoid glycoside with various biological activities. However, its effect on the pathophysiological process of MI/RI has not yet been reported. The aim of this study was to determine whether OA could alleviate MI/RI induced inflammation and pyroptosis in vivo and in vitro, providing a novel therapeutic regimen for the treatment of MI/RI. A high-throughput drug screening strategy was employed to test 2,661 natural compound libraries that can alleviate MI/RI in vivo and in vitro. The rat model of MI/RI was established by ligating the left anterior descending (LAD) coronary artery. H9c2 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate MI/RI. The results show that OA is able to significantly inhibit apoptosis, pyroptosis and the inflammation response (TNF-α, IL-6, IL-8, IL-10, IL-1β, IL-18) in vivo and in vitro, and reduce the release of myocardial enzymes (cTnI, cTnT, CK-MB, LDH, AST). In the rat MI/RI model, OA can not only improve cardiac function and reduce inflammatory cell infiltration but also reduce myocardial infarct size. The results revealed that OA is an effective remedy against MI/RI as it reduces the inflammatory response and inhibits pyroptosis. This may provide a new therapeutic target for the clinical treatment of MI/RI.

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“…In the case of verapamil, the only drug on our list with human clinical Kp,uu,brain data available, the cARLA-treated BBB model well approximated the human in vivo value (Fig. 5e) and was second only to non-human primate in vivo data among predictive models 22,25,56 .…”

Section: Carla Improves the Prediction Of Drug-and Nanoparticle Deliv...mentioning

confidence: 82%

Synergistic induction of blood-brain barrier properties

Porkoláb

Mészáros

Szecskó

et al. 2023

Preprint

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Blood-brain barrier (BBB) models derived from human stem cells are powerful tools to improve our understanding of human cerebrovascular diseases and facilitate drug development for the brain. Yet providing endothelial cells with the appropriate molecular cues to both retain a vascular identity and acquire BBB characteristics remains challenging. Here we present cARLA, an easy-to-use and affordable small molecule cocktail that robustly induces BBB properties in vitro. By activating cyclic AMP and Wnt/β-catenin signaling while inhibiting the transforming growth factor beta (TGF-β) pathway, cARLA synergistically enhances barrier tightness in a range of BBB models. We demonstrate that, upon cARLA treatment, human stem cell-derived endothelial cells have lower rates of transcytosis, higher glycocalyx density and increased efflux pump activity with a shift in gene expressional profile towards the in vivo brain endothelial signature. Our work provides mechanistic insight into how endothelial signaling is orchestrated during BBB maturation and leverages this to advance the prediction of drug delivery to the human brain.

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Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Cited by 13 publications

References 49 publications

Quantitative Targeted Absolute Proteomics for Better Characterization of an In Vitro Human Blood–Brain Barrier Model Derived from Hematopoietic Stem Cells

Quantitative Targeted Absolute Proteomics for Better Characterization of an In Vitro Human Blood–Brain Barrier Model Derived from Hematopoietic Stem Cells

Natural Compound Library Screening Identifies Oroxin A for the Treatment of Myocardial Ischemia/Reperfusion Injury

Synergistic induction of blood-brain barrier properties

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