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Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells

With increasing global health threats has come an urgent need to rapidly develop and deploy safe and effective therapies. A common practice to fast track clinical adoption of compounds for new indications is to repurpose already approved therapeutics; however, many compounds considered safe to a spe...

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Autores principales: Slavin, Ileana, Dea, Steven, Arunkumar, Priyanka, Sodhi, Neha, Montefusco, Sandro, Siqueira-Neto, Jair, Seelke, Janet, Lofstrom, Mary Anne, Anson, Blake, Zanella, Fabian, Carromeu, Cassiano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918576/
https://www.ncbi.nlm.nih.gov/pubmed/33672998
http://dx.doi.org/10.3390/ijms22041908
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author Slavin, Ileana
Dea, Steven
Arunkumar, Priyanka
Sodhi, Neha
Montefusco, Sandro
Siqueira-Neto, Jair
Seelke, Janet
Lofstrom, Mary Anne
Anson, Blake
Zanella, Fabian
Carromeu, Cassiano
author_facet Slavin, Ileana
Dea, Steven
Arunkumar, Priyanka
Sodhi, Neha
Montefusco, Sandro
Siqueira-Neto, Jair
Seelke, Janet
Lofstrom, Mary Anne
Anson, Blake
Zanella, Fabian
Carromeu, Cassiano
author_sort Slavin, Ileana
collection PubMed
description With increasing global health threats has come an urgent need to rapidly develop and deploy safe and effective therapies. A common practice to fast track clinical adoption of compounds for new indications is to repurpose already approved therapeutics; however, many compounds considered safe to a specific application or population may elicit undesirable side effects when the dosage, usage directives, and/or clinical context are changed. For example, progenitor and developing cells may have different susceptibilities than mature dormant cells, which may yet be different than mature active cells. Thus, in vitro test systems should reflect the cellular context of the native cell: developing, nascent, or functionally active. To that end, we have developed high-throughput, two- and three-dimensional human induced pluripotent stem cell (hiPSC)-derived neural screening platforms that reflect different neurodevelopmental stages. As a proof of concept, we implemented this in vitro human system to swiftly identify the potential neurotoxicity profiles of 29 therapeutic compounds that could be repurposed as anti-virals. Interestingly, many compounds displayed high toxicity on early-stage neural tissues but not on later stages. Compounds with the safest overall viability profiles were further evaluated for functional assessment in a high-throughput calcium flux assay. Of the 29 drugs tested, only four did not modulate or have other potentially toxic effects on the developing or mature neurospheroids across all the tested dosages. These results highlight the importance of employing human neural cultures at different stages of development to fully understand the neurotoxicity profile of potential therapeutics across normal ontogeny.
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spelling pubmed-79185762021-03-02 Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells Slavin, Ileana Dea, Steven Arunkumar, Priyanka Sodhi, Neha Montefusco, Sandro Siqueira-Neto, Jair Seelke, Janet Lofstrom, Mary Anne Anson, Blake Zanella, Fabian Carromeu, Cassiano Int J Mol Sci Article With increasing global health threats has come an urgent need to rapidly develop and deploy safe and effective therapies. A common practice to fast track clinical adoption of compounds for new indications is to repurpose already approved therapeutics; however, many compounds considered safe to a specific application or population may elicit undesirable side effects when the dosage, usage directives, and/or clinical context are changed. For example, progenitor and developing cells may have different susceptibilities than mature dormant cells, which may yet be different than mature active cells. Thus, in vitro test systems should reflect the cellular context of the native cell: developing, nascent, or functionally active. To that end, we have developed high-throughput, two- and three-dimensional human induced pluripotent stem cell (hiPSC)-derived neural screening platforms that reflect different neurodevelopmental stages. As a proof of concept, we implemented this in vitro human system to swiftly identify the potential neurotoxicity profiles of 29 therapeutic compounds that could be repurposed as anti-virals. Interestingly, many compounds displayed high toxicity on early-stage neural tissues but not on later stages. Compounds with the safest overall viability profiles were further evaluated for functional assessment in a high-throughput calcium flux assay. Of the 29 drugs tested, only four did not modulate or have other potentially toxic effects on the developing or mature neurospheroids across all the tested dosages. These results highlight the importance of employing human neural cultures at different stages of development to fully understand the neurotoxicity profile of potential therapeutics across normal ontogeny. MDPI 2021-02-14 /pmc/articles/PMC7918576/ /pubmed/33672998 http://dx.doi.org/10.3390/ijms22041908 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Slavin, Ileana
Dea, Steven
Arunkumar, Priyanka
Sodhi, Neha
Montefusco, Sandro
Siqueira-Neto, Jair
Seelke, Janet
Lofstrom, Mary Anne
Anson, Blake
Zanella, Fabian
Carromeu, Cassiano
Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells
title Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells
title_full Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells
title_fullStr Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells
title_full_unstemmed Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells
title_short Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells
title_sort human ipsc-derived 2d and 3d platforms for rapidly assessing developmental, functional, and terminal toxicities in neural cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918576/
https://www.ncbi.nlm.nih.gov/pubmed/33672998
http://dx.doi.org/10.3390/ijms22041908
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