Prediction of Drug Permeability Using In Vitro Blood–Brain Barrier Models with Human Induced Pluripotent Stem Cell-Derived Brain Microvascular Endothelial Cells
| Autor: | Tadanori Yamada, Hideo Fushimi, Takeshi Yamamoto, Mima Shinji, Makiko Ohshima, Shota Kamei |
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| Rok vydání: | 2019 |
| Předmět: |
0206 medical engineering
Central nervous system lcsh:Medicine 02 engineering and technology Blood–brain barrier General Biochemistry Genetics and Molecular Biology drug discovery 03 medical and health sciences chemistry.chemical_compound astrocyte medicine Original Research Article Induced pluripotent stem cell lcsh:QH301-705.5 Barrier function 030304 developmental biology 0303 health sciences neurotherapeutic drugs Drug discovery lcsh:R 020601 biomedical engineering neuron Cell biology medicine.anatomical_structure lcsh:Biology (General) chemistry cardiovascular system Neuron Xenobiotic Astrocyte |
| Zdroj: | BioResearch Open Access, Vol 8, Iss 1, Pp 200-209 (2019) BioResearch Open Access |
| ISSN: | 2164-7860 |
| DOI: | 10.1089/biores.2019.0026 |
| Popis: | The strong barrier function of the blood–brain barrier (BBB) protects the central nervous system (CNS) from xenobiotic substances, while the expression of selective transporters controls the transportation of nutrients between the blood and brain. As a result, the delivery of drugs to the CNS and prediction of the ability of specific drugs to penetrate the BBB can be difficult. Although in vivo pharmacokinetic analysis using rodents is a commonly used method for predicting human BBB permeability, novel in vitro BBB models, such as Transwell models, have been developed recently. Induced pluripotent stem cells (iPSCs) have the potential to differentiate into various types of cells, and protocols for the differentiation of iPSCs to generate brain microvascular endothelial cells (BMECs) have been reported. The use of iPSCs makes it easy to scale-up iPSC-derived BMECs (iBMECs) and enables production of BBB disease models by using iPSCs from multiple donors with disease, which are advantageous properties compared with models that utilize primary BMECs (pBMECs). There has been little research on the value of iBMECs for predicting BBB permeability. This study focused on the similarity of iBMECs to pBMECs and investigated the ability of iPSC-BBB models (monoculture and coculture) to predict in vivo human BBB permeability using iBMECs. iBMECs express BMEC markers (e.g., VE-cadherin and claudin-5) and influx/efflux transporters (e.g., Glut-1, SLC7A5, CD220, P-gp, ABCG2, and MRP-1) and exhibit high barrier function (transendothelial electrical resistance, >1000 Ω × cm2) as well as similar transporter expression profiles to pBMECs. We determined that the efflux activity using P-glycoprotein (P-gp) transporter is not sufficient in iBMECs, while in drug permeability tests, iPSC-derived BBB models showed a higher correlation with in vivo human BBB permeability compared with a rat BBB model and the Caco-2 model. In a comparison between monoculture and coculture models, the coculture BBB model showed higher efflux activity for compounds with low CNS permeability (e.g., verapamil and thioridazine). In conclusion, iPSC-BBB models make it possible to predict BBB permeability, and employing coculturing can improve iPSC-BBB function. |
| Databáze: | OpenAIRE |
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