TY  - JOUR
AU  - Fengler, Sven
AU  - Kurkowsky, Birgit
AU  - Kaushalya, Sanjeev Kumar
AU  - Roth, Wera
AU  - Fava, Eugenio
AU  - Denner, Philip
TI  - Human iPSC-derived brain endothelial microvessels in a multi-well format enable permeability screens of anti-inflammatory drugs.
JO  - Biomaterials
VL  - 286
SN  - 0142-9612
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DZNE-2022-01092
SP  - 121525
PY  - 2022
N1  - (CC BY-NC-ND)
AB  - Optimizing drug candidates for blood-brain barrier (BBB) penetration remains one of the key challenges in drug discovery to finally target brain disorders including neurodegenerative diseases which do not have adequate treatments so far. It has been difficult to establish state-of-the-art stem cell derived in vitro models that mimic physiological barrier properties including a 3D microvasculature in a format that is scalable to screen drugs for BBB penetration. To address this challenge, we established human induced pluripotent stem cell (iPSC)-derived brain endothelial microvessels in a standardized and scalable multi-well plate format. iPSC-derived brain microvascular endothelial cells (BMECs) were supplemented with primary cell conditioned media and grew to microvessels in 10 days. Produced microvessels show typical BBB endothelial protein expression, tight-junctions and polarized localization of efflux transporter. Microvessels exhibited physiological relevant trans-endothelial electrical resistance (TEER), were leak-tight for 10 kDa dextran-Alexa 647 and strongly limited the permeability of sodium fluorescein (NaF). Permeability tests with reference compounds confirmed the suitability of our model as platform to identify potential BBB penetrating anti-inflammatory drugs. The here presented platform recapitulates physiological properties and allows rapid screening of BBB permeable anti-inflammatory compounds that has been suggested as promising substances to cure so far untreatable neurodegenerative diseases.
KW  - Anti-Inflammatory Agents: metabolism
KW  - Anti-Inflammatory Agents: pharmacology
KW  - Blood-Brain Barrier: metabolism
KW  - Brain: physiology
KW  - Cell Differentiation: physiology
KW  - Cells, Cultured
KW  - Endothelial Cells: metabolism
KW  - Humans
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Microvessels: metabolism
KW  - Permeability
KW  - 3D microvessel (Other)
KW  - Blood-brain barrier chip (Other)
KW  - Conditioned medium (Other)
KW  - Drug permeability (Other)
KW  - High-content microfluidic (Other)
KW  - Induced pluripotent stem cells (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35599022
DO  - DOI:10.1016/j.biomaterials.2022.121525
UR  - https://pub.dzne.de/record/164543
ER  -