Expression and Functional Characterization of Drug Transporters in Brain Microvascular Endothelial Cells Derived from Human Induced Pluripotent Stem Cells

Brain microvascular endothelial cells derived from human induced pluripotent stem cells (hiPS-BMECs) have been proposed as a new blood–brain barrier model, but their transport function has not been fully clarified. Therefore, in this study, we investigated the gene expression and function of transpo...

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Published in:Molecular pharmaceutics 2018-12, Vol.15 (12), p.5546-5555
Main Authors: Kurosawa, Toshiki, Tega, Yuma, Higuchi, Kei, Yamaguchi, Tomoko, Nakakura, Takashi, Mochizuki, Tatsuki, Kusuhara, Hiroyuki, Kawabata, Kenji, Deguchi, Yoshiharu
Format: Article
Language:English
Subjects:
Arginine - pharmacokinetics
Blood-Brain Barrier - metabolism
Cell Differentiation
Cell Line
Cell Membrane Permeability - drug effects
Endothelial Cells - metabolism
Glutamic Acid - pharmacokinetics
Humans
Induced Pluripotent Stem Cells - physiology
Lactic Acid - pharmacokinetics
Membrane Transport Proteins - genetics
Membrane Transport Proteins - metabolism
Microvessels - cytology
Prazosin - pharmacokinetics
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - isolation & purification
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Summary:Brain microvascular endothelial cells derived from human induced pluripotent stem cells (hiPS-BMECs) have been proposed as a new blood–brain barrier model, but their transport function has not been fully clarified. Therefore, in this study, we investigated the gene expression and function of transporters in hiPS-BMECs by means of quantitative reverse transcription-PCR, in vitro transcellular transport studies, and uptake experiments. mRNAs encoding ABC and SLC transporters, such as BCRP, MCT1, CAT1, and GLAST, were highly expressed in hiPS-BMECs. Transcellular transport studies showed that prazosin, [14C]l-lactate, [3H]l-arginine, and [3H]l-glutamate (substrates of BCRP, MCT1, CAT1, and GLAST, respectively) were transported asymmetrically across the hiPS-BMEC monolayer. Substrates of LAT1, OCTN2, CAT1, GLAST, MCT1, and proton-coupled organic cation (H+/OC) antiporter were taken up by hiPS-BMECs in a time-, temperature-, and concentration-dependent manner, and the uptakes were markedly decreased by inhibitors of the corresponding transporter. These results indicate that hiPS-BMECs express multiple nutrient and drug transporters.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.8b00697