Dataset Information

A Human Stem Cell-Derived Brain-Liver Chip for Assessing Blood-Brain-Barrier Permeation of Pharmaceutical Drugs.

ABSTRACT: Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier model with a cortical brain and a liver spheroid model from the same donor in a closed microfluidic system (MPS). The two model compounds atenolol and propranolol were used to measure permeation at the blood-brain barrier and to assess metabolization. Both substances showed an in vivo-like permeation behavior and were metabolized in vitro. Therefore, the novel multi-organ system enabled not only the measurement of parent compound concentrations but also of metabolite distribution at the blood-brain barrier.

SUBMITTER: Koenig L

PROVIDER: S-EPMC9600760 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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A Human Stem Cell-Derived Brain-Liver Chip for Assessing Blood-Brain-Barrier Permeation of Pharmaceutical Drugs.

Koenig Leopold L Ramme Anja Patricia AP Faust Daniel D Mayer Manuela M Flötke Tobias T Gerhartl Anna A Brachner Andreas A Neuhaus Winfried W Appelt-Menzel Antje A Metzger Marco M Marx Uwe U Dehne Eva-Maria EM

Cells 20221019 20

Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced plu ...[more]

PMID: 36291161

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Project description:Studies of neonatal neural pathologies and development of appropriate therapeutics are hampered by a lack of relevant in vitro models of neonatal blood-brain barrier (BBB). To establish such a model, we have developed a novel blood-brain barrier on a chip (B3C) that comprises a tissue compartment and vascular channels placed side-by-side mimicking the three-dimensional morphology, size and flow characteristics of microvessels in vivo. Rat brain endothelial cells (RBEC) isolated from neonatal rats were seeded in the vascular channels of B3C and maintained under shear flow conditions, while neonatal rat astrocytes were cultured under static conditions in the tissue compartment of the B3C. RBEC formed continuous endothelial lining with a central lumen along the length of the vascular channels of B3C and exhibited tight junction formation, as measured by the expression of zonula occludens-1 (ZO-1). ZO-1 expression significantly increased with shear flow in the vascular channels and with the presence of astrocyte conditioned medium (ACM) or astrocytes cultured in the tissue compartment. Consistent with in vivo BBB, B3C allowed endfeet-like astrocyte-endothelial cell interactions through a porous interface that separates the tissue compartment containing cultured astrocytes from the cultured RBEC in the vascular channels. The permeability of fluorescent 40 kDa dextran from vascular channel to the tissue compartment significantly decreased when RBEC were cultured in the presence of astrocytes or ACM (from 41.0 ± 0.9 x 10-6 cm/s to 2.9 ± 1.0 x 10-6 cm/s or 1.1±0.4 x 10-6 cm/s, respectively). Measurement of electrical resistance in B3C further supports that the addition of ACM significantly improves the barrier function in neonatal RBEC. Moreover, B3C exhibits significantly improved barrier characteristics compared to the transwell model and B3C permeability was not significantly different from the in vivo BBB permeability in neonatal rats. In summary, we developed a first dynamic in vitro neonatal BBB on a chip (B3C) that closely mimics the in vivo microenvironment, offers the flexibility of real time analysis, and is suitable for studies of BBB function as well as screening of novel therapeutics.

Project description:Daily exposure to xenobiotics affects human health, especially the nervous system, causing neurodegenerative diseases. The nervous system is protected by tight junctions present at the blood-brain barrier (BBB), but only molecules with desirable physicochemical properties can permeate it. This is why permeation is a decisive step in avoiding unwanted brain toxicity and also in developing neuronal drugs. In silico methods are being implemented as an initial step to reduce animal testing and the time complexity of the in vitro screening process. However, most in silico methods are ligand based, and consider only the physiochemical properties of ligands. However, these ligand-based methods have their own limitations and sometimes fail to predict the BBB permeation of xenobiotics. The objective of this work was to investigate the influence of the pharmacophoric features of protein-ligand interactions on BBB permeation. For these purposes, receptor-based pharmacophore and ligand-based pharmacophore fingerprints were developed using docking and Rdkit, respectively. Then, these fingerprints were trained on classical machine-learning models and compared with classical fingerprints. Among the tested footprints, the ligand-based pharmacophore fingerprint achieved slightly better (77% accuracy) performance compared to the classical fingerprint method. In contrast, receptor-based pharmacophores did not lead to much improvement compared to classical descriptors. The performance can be further improved by considering efflux proteins such as BCRP (breast cancer resistance protein), as well as P-gp (P-glycoprotein). However, the limited data availability for other proteins regarding their pharmacophoric interactions is a bottleneck to its improvement. Nonetheless, the developed models and exploratory analysis provide a path to extend the same framework for environmental chemicals, which, like drugs, are also xenobiotics. This research can help in human health risk assessment by a priori screening for neurotoxicity-causing agents.

Dataset Information

A Human Stem Cell-Derived Brain-Liver Chip for Assessing Blood-Brain-Barrier Permeation of Pharmaceutical Drugs.

Publications

A Human Stem Cell-Derived Brain-Liver Chip for Assessing Blood-Brain-Barrier Permeation of Pharmaceutical Drugs.

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