Journal Article

DZNE-2022-01092

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Human iPSC-derived brain endothelial microvessels in a multi-well format enable permeability screens of anti-inflammatory drugs.

Fengler, S. (First author)DZNE* ; Kurkowsky, B.DZNE* ; Kaushalya, S. K.DZNE* ; Roth, W.DZNE* ; Fava, E.DZNE* ; Denner, P. (Last author)DZNE*

2022
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.biomaterials.2022.121525

Abstract: 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.

Keyword(s): Anti-Inflammatory Agents: metabolism (MeSH) ; Anti-Inflammatory Agents: pharmacology (MeSH) ; Blood-Brain Barrier: metabolism (MeSH) ; Brain: physiology (MeSH) ; Cell Differentiation: physiology (MeSH) ; Cells, Cultured (MeSH) ; Endothelial Cells: metabolism (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Microvessels: metabolism (MeSH) ; Permeability (MeSH) ; 3D microvessel ; Blood-brain barrier chip ; Conditioned medium ; Drug permeability ; High-content microfluidic ; Induced pluripotent stem cells

Note: (CC BY-NC-ND)

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Contributing Institute(s):

1. Systems Phenomics (AG Fava 1)
2. Laboratory Automation Technologies (LAT) (LAT)
3. Light Microscopy Facility (LMF) (LMF)
4. Leitung Core Facilities (AG Fava 2)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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