Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound

Sara Wellens; Lucie Dehouck; Vidya Chandrasekaran; Pranika Singh; Rodrigo Azevedo Loiola; Emmanuel Sevin; Thomas Exner; Paul Jennings; Fabien Gosselet; Maxime Culot

doi:10.1016/j.tiv.2021.105112

Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound

Sara Wellens
, Lucie Dehouck
, Vidya Chandrasekaran
, Pranika Singh
, Rodrigo Azevedo Loiola
, Emmanuel Sevin
, Thomas Exner
, Paul Jennings
, Fabien Gosselet
, Maxime Culot^*

^*Corresponding author for this work

AIMMS

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

The blood-brain barrier (BBB) is a highly restrictive barrier that preserves central nervous system homeostasis and ensures optimal brain functioning. Using BBB cell assays makes it possible to investigate whether a compound is likely to compromise BBBs functionality, thereby probably resulting in neurotoxicity. Recently, several protocols to obtain human brain-like endothelial cells (BLECs) from induced pluripotent stem cells (iPSCs) have been reported. Within the framework of the European MSCA-ITN in3 project, we explored the possibility to use an iPSC-derived BBB model to assess the effects of repeated dose treatment with chemicals, using Cyclosporine A (CsA) as a model compound. The BLECs were found to exhibit important BBB characteristics up to 15 days after the end of the differentiation and could be used to assess the effects of repeated dose treatment. Although BLECs were still undergoing transcriptional changes over time, a targeted transcriptome analysis (TempO-Seq) indicated a time and concentration dependent activation of ATF4, XBP1, Nrf2 and p53 stress response pathways under CsA treatment. Taken together, these results demonstrate that this iPSC-derived BBB model and iPSC-derived models in general hold great potential to study the effects of repeated dose exposure with chemicals, allowing personalized and patient-specific studies in the future.

Original language	English
Article number	105112
Pages (from-to)	1-11
Number of pages	11
Journal	Toxicology in Vitro
Volume	73
Early online date	22 Feb 2021
DOIs	https://doi.org/10.1016/j.tiv.2021.105112
Publication status	Published - Jun 2021

Bibliographical note

Publisher Copyright:
© 2021

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

We would like to thank Anja Wilmes (Division of Molecular and Computational Toxicology, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, The Netherlands) and Marie-Gabrielle Zurich (Department of Physiology, University of Lausanne, Switzerland) for their feedback and suggestions. The work was funded by the Marie Sklodowska-Curie Action-Innovative Training Network project in3, under grant no. 721975 (fellowship to Sara Wellens, Vidya Chandrasekaran and Pranika Singh). Fabien Gosselet and Rodrigo Azevedo Loiola were partially supported by the Euronanomed 8th Joint Call-MAGBBRIS collaborative project by grants from the French national agency (ANR-ANR-17-ENM3-0005-01). The work was funded by the Marie Sklodowska-Curie Action-Innovative Training Network project in3, under grant no. 721975 (fellowship to Sara Wellens, Vidya Chandrasekaran and Pranika Singh). Fabien Gosselet and Rodrigo Azevedo Loiola were partially supported by the Euronanomed 8th Joint Call-MAGBBRIS collaborative project by grants from the French national agency ( ANR-ANR-17-ENM3-0005-01 ).

Funders	Funder number
Marie-Gabrielle Zurich
Horizon 2020 Framework Programme	721975
French national agency	ANR-ANR-17-ENM3-0005-01
European Commission	115439

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Blood-brain barrier
Cyclosporine A
iPSC
Repeated dose toxicity testing
Stress-response pathways
Targeted transcriptomics

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10.1016/j.tiv.2021.105112

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title = "Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound",

abstract = "The blood-brain barrier (BBB) is a highly restrictive barrier that preserves central nervous system homeostasis and ensures optimal brain functioning. Using BBB cell assays makes it possible to investigate whether a compound is likely to compromise BBBs functionality, thereby probably resulting in neurotoxicity. Recently, several protocols to obtain human brain-like endothelial cells (BLECs) from induced pluripotent stem cells (iPSCs) have been reported. Within the framework of the European MSCA-ITN in3 project, we explored the possibility to use an iPSC-derived BBB model to assess the effects of repeated dose treatment with chemicals, using Cyclosporine A (CsA) as a model compound. The BLECs were found to exhibit important BBB characteristics up to 15 days after the end of the differentiation and could be used to assess the effects of repeated dose treatment. Although BLECs were still undergoing transcriptional changes over time, a targeted transcriptome analysis (TempO-Seq) indicated a time and concentration dependent activation of ATF4, XBP1, Nrf2 and p53 stress response pathways under CsA treatment. Taken together, these results demonstrate that this iPSC-derived BBB model and iPSC-derived models in general hold great potential to study the effects of repeated dose exposure with chemicals, allowing personalized and patient-specific studies in the future.",

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AU - Singh, Pranika

AU - Loiola, Rodrigo Azevedo

AU - Sevin, Emmanuel

AU - Exner, Thomas

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AB - The blood-brain barrier (BBB) is a highly restrictive barrier that preserves central nervous system homeostasis and ensures optimal brain functioning. Using BBB cell assays makes it possible to investigate whether a compound is likely to compromise BBBs functionality, thereby probably resulting in neurotoxicity. Recently, several protocols to obtain human brain-like endothelial cells (BLECs) from induced pluripotent stem cells (iPSCs) have been reported. Within the framework of the European MSCA-ITN in3 project, we explored the possibility to use an iPSC-derived BBB model to assess the effects of repeated dose treatment with chemicals, using Cyclosporine A (CsA) as a model compound. The BLECs were found to exhibit important BBB characteristics up to 15 days after the end of the differentiation and could be used to assess the effects of repeated dose treatment. Although BLECs were still undergoing transcriptional changes over time, a targeted transcriptome analysis (TempO-Seq) indicated a time and concentration dependent activation of ATF4, XBP1, Nrf2 and p53 stress response pathways under CsA treatment. Taken together, these results demonstrate that this iPSC-derived BBB model and iPSC-derived models in general hold great potential to study the effects of repeated dose exposure with chemicals, allowing personalized and patient-specific studies in the future.

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Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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