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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doaj-3fafc522595e473c9de7213b4e759c512021-07-15T08:21:30ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992021-07-011410.3389/fnmol.2021.715054715054Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain OrganoidsHenrik Renner0Katharina J. Becker1Katharina J. Becker2Theresa E. Kagermeier3Theresa E. Kagermeier4Martha Grabos5Farsam Eliat6Farsam Eliat7Patrick Günther8Patrick Günther9Hans R. Schöler10Jan M. Bruder11Department for Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, GermanyDepartment for Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, GermanyWestfälische Wilhelms-Universität Münster, Münster, GermanyDepartment for Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, GermanyWestfälische Wilhelms-Universität Münster, Münster, GermanyDepartment for Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, GermanyDepartment for Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, GermanyWestfälische Wilhelms-Universität Münster, Münster, GermanyDepartment for Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, GermanyWestfälische Wilhelms-Universität Münster, Münster, GermanyDepartment for Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, GermanyDepartment for Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, GermanyToxicity 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.https://www.frontiersin.org/articles/10.3389/fnmol.2021.715054/fullorganoidsmidbrainscreeninghigh throughputautomationtoxicity testing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Henrik Renner Katharina J. Becker Katharina J. Becker Theresa E. Kagermeier Theresa E. Kagermeier Martha Grabos Farsam Eliat Farsam Eliat Patrick Günther Patrick Günther Hans R. Schöler Jan M. Bruder |
spellingShingle |
Henrik Renner Katharina J. Becker Katharina J. Becker Theresa E. Kagermeier Theresa E. Kagermeier Martha Grabos Farsam Eliat Farsam Eliat Patrick Günther Patrick Günther Hans R. Schöler Jan M. Bruder Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids Frontiers in Molecular Neuroscience organoids midbrain screening high throughput automation toxicity testing |
author_facet |
Henrik Renner Katharina J. Becker Katharina J. Becker Theresa E. Kagermeier Theresa E. Kagermeier Martha Grabos Farsam Eliat Farsam Eliat Patrick Günther Patrick Günther Hans R. Schöler Jan M. Bruder |
author_sort |
Henrik Renner |
title |
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_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_sort |
cell-type-specific high throughput toxicity testing in human midbrain organoids |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Molecular Neuroscience |
issn |
1662-5099 |
publishDate |
2021-07-01 |
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. |
topic |
organoids midbrain screening high throughput automation toxicity testing |
url |
https://www.frontiersin.org/articles/10.3389/fnmol.2021.715054/full |
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