Development of Human in vitro Brain-blood Barrier Model from Induced Pluripotent Stem Cell-derived Endothelial Cells to Predict the in vivo Permeability of Drugs.
10.1007/s12264-019-00384-7
- Author:
Yuan LI
1
;
Xueying SUN
2
;
Houfu LIU
2
;
Liang HUANG
2
;
Guofeng MENG
2
;
Yu DING
3
;
Wenji SU
2
;
Jiaqi LU
2
;
Sophie GONG
2
;
Georg C TERSTAPPEN
4
;
Ru ZHANG
5
;
Wandong ZHANG
6
Author Information
1. Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Bio-medicine, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
2. Platform Technology & Sciences, GlaxoSmithKline China R&D Centre, Shanghai, 201203, China.
3. Neurosciences Therapeutic Area Unit, GlaxoSmithKline China R&D Centre, Shanghai, 201203, China.
4. Platform Technology & Sciences, GlaxoSmithKline China R&D Centre, Shanghai, 201203, China. georg.c.terstappen@gsk.com.
5. Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Bio-medicine, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. ru.zhang@tongji.edu.cn.
6. Platform Technology & Sciences, GlaxoSmithKline China R&D Centre, Shanghai, 201203, China. wzhan2@uottawa.ca.
- Publication Type:Journal Article
- Keywords:
Blood-brain barrier;
Cell differentiation;
Drug transport;
Induced pluripotent stem cell;
Prediction of in vivo permeability
- From:
Neuroscience Bulletin
2019;35(6):996-1010
- CountryChina
- Language:English
-
Abstract:
An in vitro blood-brain barrier (BBB) model is critical for enabling rapid screening of the BBB permeability of the drugs targeting on the central nervous system. Though many models have been developed, their reproducibility and renewability remain a challenge. Furthermore, drug transport data from many of the models do not correlate well with the data for in vivo BBB drug transport. Induced-pluripotent stem cell (iPSC) technology provides reproducible cell resources for in vitro BBB modeling. Here, we generated a human in vitro BBB model by differentiating the human iPSC (hiPSC) line GM25256 into brain endothelial-type cells. The model displayed BBB characteristics including tight junction proteins (ZO-1, claudin-5, and occludin) and endothelial markers (von Willebrand factor and Ulex), as well as high trans-endothelial electrical resistance (TEER) (1560 Ω.cm ± 230 Ω.cm) and γ-GTPase activity. Co-culture with primary rat astrocytes significantly increased the TEER of the model (2970 Ω.cm to 4185 Ω.cm). RNAseq analysis confirmed the expression of key BBB-related genes in the hiPSC-derived endothelial cells in comparison with primary human brain microvascular endothelial cells, including P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP). Drug transport assays for nine CNS compounds showed that the permeability of non-Pgp/BCRP and Pgp/BCRP substrates across the model was strongly correlated with rodent in situ brain perfusion data for these compounds (R = 0.982 and R = 0.9973, respectively), demonstrating the functionality of the drug transporters in the model. Thus, this model may be used to rapidly screen CNS compounds, to predict the in vivo BBB permeability of these compounds and to study the biology of the BBB.
