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Molecular and functional characterization of different BrainSphere models for use in neurotoxicity testing on microelectrode arrays

Hartmann, Julia, Henschel, Noah, Bartmann, Kristina, Dönmez, Arif, Brockerhoff, Gabriele, Koch, Katharina, Fritsche, Ellen·2023·Cells
DOI 10.3390/cells12091270PMC PMC10177384

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Abstract

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100% NESTIN-positive hiPSC-derived neural progenitor cells (hiNPCs), though with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed to apply such MEA-based spike sorting. These models are promising tools not only in toxicology but also for drug development and disease modeling.

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Cited by

Sorted by citations

Authors
Hartmann, J., Henschel, N., Bartmann, K., Dönmez, A., Brockerhoff, G., Koch, K., & Fritsche, E.
Affiliations
IUF—Leibniz-Research Institute for Environmental Medicine, Auf’m Hennekamp 50, 40225 Duesseldorf, Germany
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2023-04-27
Volume
12
Issue
9
Pages
1270
ISSN
2073-4409
DOI
10.3390/cells12091270
PMC
PMC10177384
Cited by
30
References
5
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Ministry for innovation, science and research of the State of North-Rhine Westphalia, Germany (233-1.08.03.03-121972, MST-66-00205, 101057014, 825759)
  • Danish Environmental Protection Agency (EPA) (233-1.08.03.03-121972, MST-66-00205, 101057014, 825759)
  • Horizon Europe project PARC (233-1.08.03.03-121972, MST-66-00205, 101057014, 825759)
  • European Union’s Horizon 2020 Research and Innovation Program (233-1.08.03.03-121972, MST-66-00205, 101057014, 825759)

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