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Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids

Toxicity testing is a crucial step in the development and approval of chemical compounds for human contact and consumption. However, existing model systems often fall short in their prediction of human toxicity in vivo because they may not sufficiently recapitulate human physiology. The complexity o...

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Autores principales: Renner, Henrik, Becker, Katharina J., Kagermeier, Theresa E., Grabos, Martha, Eliat, Farsam, Günther, Patrick, Schöler, Hans R., Bruder, Jan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321240/
https://www.ncbi.nlm.nih.gov/pubmed/34335182
http://dx.doi.org/10.3389/fnmol.2021.715054
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author Renner, Henrik
Becker, Katharina J.
Kagermeier, Theresa E.
Grabos, Martha
Eliat, Farsam
Günther, Patrick
Schöler, Hans R.
Bruder, Jan M.
author_facet Renner, Henrik
Becker, Katharina J.
Kagermeier, Theresa E.
Grabos, Martha
Eliat, Farsam
Günther, Patrick
Schöler, Hans R.
Bruder, Jan M.
author_sort Renner, Henrik
collection PubMed
description Toxicity testing is a crucial step in the development and approval of chemical compounds for human contact and consumption. However, existing model systems often fall short in their prediction of human toxicity in vivo because they may not sufficiently recapitulate human physiology. The complexity of three-dimensional (3D) human organ-like cell culture systems (“organoids”) can generate potentially more relevant models of human physiology and disease, including toxicity predictions. However, so far, the inherent biological heterogeneity and cumbersome generation and analysis of organoids has rendered efficient, unbiased, high throughput evaluation of toxic effects in these systems challenging. Recent advances in both standardization and quantitative fluorescent imaging enabled us to dissect the toxicities of compound exposure to separate cellular subpopulations within human organoids at the single-cell level in a framework that is compatible with high throughput approaches. Screening a library of 84 compounds in standardized human automated midbrain organoids (AMOs) generated from two independent cell lines correctly recognized known nigrostriatal toxicants. This approach further identified the flame retardant 3,3′,5,5′-tetrabromobisphenol A (TBBPA) as a selective toxicant for dopaminergic neurons in the context of human midbrain-like tissues for the first time. Results were verified with high reproducibility in more detailed dose-response experiments. Further, we demonstrate higher sensitivity in 3D AMOs than in 2D cultures to the known neurotoxic effects of the pesticide lindane. Overall, the automated nature of our workflow is freely scalable and demonstrates the feasibility of quantitatively assessing cell-type-specific toxicity in human organoids in vitro.
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spelling pubmed-83212402021-07-30 Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids Renner, Henrik Becker, Katharina J. Kagermeier, Theresa E. Grabos, Martha Eliat, Farsam Günther, Patrick Schöler, Hans R. Bruder, Jan M. Front Mol Neurosci Molecular Neuroscience Toxicity testing is a crucial step in the development and approval of chemical compounds for human contact and consumption. However, existing model systems often fall short in their prediction of human toxicity in vivo because they may not sufficiently recapitulate human physiology. The complexity of three-dimensional (3D) human organ-like cell culture systems (“organoids”) can generate potentially more relevant models of human physiology and disease, including toxicity predictions. However, so far, the inherent biological heterogeneity and cumbersome generation and analysis of organoids has rendered efficient, unbiased, high throughput evaluation of toxic effects in these systems challenging. Recent advances in both standardization and quantitative fluorescent imaging enabled us to dissect the toxicities of compound exposure to separate cellular subpopulations within human organoids at the single-cell level in a framework that is compatible with high throughput approaches. Screening a library of 84 compounds in standardized human automated midbrain organoids (AMOs) generated from two independent cell lines correctly recognized known nigrostriatal toxicants. This approach further identified the flame retardant 3,3′,5,5′-tetrabromobisphenol A (TBBPA) as a selective toxicant for dopaminergic neurons in the context of human midbrain-like tissues for the first time. Results were verified with high reproducibility in more detailed dose-response experiments. Further, we demonstrate higher sensitivity in 3D AMOs than in 2D cultures to the known neurotoxic effects of the pesticide lindane. Overall, the automated nature of our workflow is freely scalable and demonstrates the feasibility of quantitatively assessing cell-type-specific toxicity in human organoids in vitro. Frontiers Media S.A. 2021-07-15 /pmc/articles/PMC8321240/ /pubmed/34335182 http://dx.doi.org/10.3389/fnmol.2021.715054 Text en Copyright © 2021 Renner, Becker, Kagermeier, Grabos, Eliat, Günther, Schöler and Bruder. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Neuroscience
Renner, Henrik
Becker, Katharina J.
Kagermeier, Theresa E.
Grabos, Martha
Eliat, Farsam
Günther, Patrick
Schöler, Hans R.
Bruder, Jan M.
Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids
title Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids
title_full Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids
title_fullStr Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids
title_full_unstemmed Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids
title_short Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids
title_sort cell-type-specific high throughput toxicity testing in human midbrain organoids
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321240/
https://www.ncbi.nlm.nih.gov/pubmed/34335182
http://dx.doi.org/10.3389/fnmol.2021.715054
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