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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/4/1908 |
| _version_ | 1797396552213331968 |
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| author | Ileana Slavin Steven Dea Priyanka Arunkumar Neha Sodhi Sandro Montefusco Jair Siqueira-Neto Janet Seelke Mary Anne Lofstrom Blake Anson Fabian Zanella Cassiano Carromeu |
| author_facet | Ileana Slavin Steven Dea Priyanka Arunkumar Neha Sodhi Sandro Montefusco Jair Siqueira-Neto Janet Seelke Mary Anne Lofstrom Blake Anson Fabian Zanella Cassiano Carromeu |
| author_sort | Ileana Slavin |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T00:53:01Z |
| format | Article |
| id | doaj.art-e1ea4556e8d64a8390882339fe1a6956 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:53:01Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e1ea4556e8d64a8390882339fe1a69562023-12-11T17:06:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01224190810.3390/ijms22041908Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural CellsIleana Slavin0Steven Dea1Priyanka Arunkumar2Neha Sodhi3Sandro Montefusco4Jair Siqueira-Neto5Janet Seelke6Mary Anne Lofstrom7Blake Anson8Fabian Zanella9Cassiano Carromeu10StemoniX, La Jolla, CA 92037, USAStemoniX, La Jolla, CA 92037, USAStemoniX, La Jolla, CA 92037, USAStemoniX, La Jolla, CA 92037, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USAStemoniX, La Jolla, CA 92037, USAStemoniX, La Jolla, CA 92037, USAStemoniX, La Jolla, CA 92037, USAStemoniX, La Jolla, CA 92037, USAStemoniX, La Jolla, CA 92037, USAWith 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.https://www.mdpi.com/1422-0067/22/4/1908human induced pluripotent stem cells (hiPSCs)drug discoveryneurodevelopmental toxicityrepurposed drugsorganoids |
| spellingShingle | Ileana Slavin Steven Dea Priyanka Arunkumar Neha Sodhi Sandro Montefusco Jair Siqueira-Neto Janet Seelke Mary Anne Lofstrom Blake Anson Fabian Zanella Cassiano Carromeu Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells International Journal of Molecular Sciences human induced pluripotent stem cells (hiPSCs) drug discovery neurodevelopmental toxicity repurposed drugs organoids |
| 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 | human induced pluripotent stem cells (hiPSCs) drug discovery neurodevelopmental toxicity repurposed drugs organoids |
| url | https://www.mdpi.com/1422-0067/22/4/1908 |
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