Incorporation of stem cell-derived astrocytes into neuronal organoids to allow neuro-glial interactions in toxicological studies

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2020
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Loser, Dominik
Kraushaar, Udo
Britschgi, Markus
Patsch, Christoph
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Alternatives to Animal Experimentation : ALTEX. Springer Spektrum. 2020, 37(3). ISSN 1868-596X. eISSN 1868-596X. Available under: doi: 10.14573/altex.1911111
Zusammenfassung

Human cell-based neural organoids are increasingly being used for investigations of neurotoxicity, and to study the pathophysiology of neurodegenerative diseases. Here, we present a fast and robust method to generate 3D cultured human dopaminergic neurons (LUHMES) for toxicity testing and long-term culture. Moreover, a plating step was introduced to allow generation of neurite networks with defined 2D orientation and several mm length, while all cell bodies (somata) remained in a 3D, dome-like structure. These cultures, named here 2.5D (for 2.5 dimensional), offer new approaches to quantify toxicant effects on organoids by standard technology and high throughput. For instance, the system reacted to the parkinsonian model toxicants MPP+, rotenone, MG-132 and the ferroptosis-inducer erastin. Moreover, stable incorporation of human stem cell-derived astrocytes or microglia was possible. Added astrocytes stabilized the post mitotic state of the LUHMES neurons and thereby allowed the formation of a stable micro-physiological system. We observed neuroprotection against the proteasome inhibitor MG-132 and the ferroptosis-inducer erastin by such glia. This exemplifies the crucial protective role of astrocytes in neurodegeneration. The modularity of the system was further employed to incorporate microglia together with astrocytes into the organoids. Such ratio-defined, three cell type-based organoids will allow new approaches to study human pathophysiology and toxicology of the nervous system.

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ISO 690BRÜLL, Markus, Anna-Sophie SPRENG, Simon GUTBIER, Dominik LOSER, Alice KREBS, Marvin REICH, Udo KRAUSHAAR, Markus BRITSCHGI, Christoph PATSCH, Marcel LEIST, 2020. Incorporation of stem cell-derived astrocytes into neuronal organoids to allow neuro-glial interactions in toxicological studies. In: Alternatives to Animal Experimentation : ALTEX. Springer Spektrum. 2020, 37(3). ISSN 1868-596X. eISSN 1868-596X. Available under: doi: 10.14573/altex.1911111
BibTex
@article{Brull2020Incor-49092,
  year={2020},
  doi={10.14573/altex.1911111},
  title={Incorporation of stem cell-derived astrocytes into neuronal organoids to allow neuro-glial interactions in toxicological studies},
  number={3},
  volume={37},
  issn={1868-596X},
  journal={Alternatives to Animal Experimentation : ALTEX},
  author={Brüll, Markus and Spreng, Anna-Sophie and Gutbier, Simon and Loser, Dominik and Krebs, Alice and Reich, Marvin and Kraushaar, Udo and Britschgi, Markus and Patsch, Christoph and Leist, Marcel}
}
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