RRC ID 77420
Author Yamaguchi T, Sako D, Kurosawa T, Nishijima M, Miyano A, Kubo Y, Ohtsuki S, Kawabata K, Deguchi Y.
Title Development and Functional Evaluation of MDR1-expressing Microvascular Endothelial-like Cells Derived from Human iPS Cells as an In vitro Blood-brain Barrier Model.
Journal J Pharm Sci
Abstract In order to establish an in vitro model of the human blood-brain barrier (BBB), MDR1-overexpressing human induced pluripotent stem cells (hiPSCs) were generated, and they were differentiated to MDR1-expressing brain microvascular endothelial-like cells (MDR1-expressing hiPS-BMECs). MDR1-expressing hiPS-BMECs monolayers showed good barrier function in terms of tight junction protein expression and trans-epithelial electrical resistance (TEER). In sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS), MDR1 protein expression was markedly increased in MDR1-expressing hiPS-BMECs, whereas other ABC and SLC transporters showed almost identical expression between MDR1-expressing hiPS-BMECs and mock hiPS-BMECs, suggesting that MDR1 overexpression had little or no knock-on effect on other proteins. The basolateral-to-apical transport of MDR1 substrates, such as quinidine, [3H]digoxin and [3H]vinblastine, was higher than the apical-to-basolateral transport, and the efflux-dominant transport was attenuated by PSC833, an MDR1-specific inhibitor, indicating that MDR1-mediated efflux transport is functional. The robust MDR1 function was also supported by the efflux-dominant transports of [3H]cyclosporin A, loperamide, cetirizine, and verapamil by MDR1-expressing hiPS-BMECs. These results suggest that MDR1-expressing hiPS-BMECs can be used as an in vitro model of the human BBB.
Volume 112(12)
Pages 3216-3223
Published 2023-12-1
DOI 10.1016/j.xphs.2023.09.004
PII S0022-3549(23)00365-9
PMID 37690777
MeSH Blood-Brain Barrier* Brain Cell Line Cells, Cultured Humans Induced Pluripotent Stem Cells*
IF 2.997
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)