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Open AccessArticle

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

1
StemoniX, La Jolla, CA 92037, USA
2
Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Maurizio Memo
Int. J. Mol. Sci. 2021, 22(4), 1908; https://doi.org/10.3390/ijms22041908
Received: 4 January 2021 / Revised: 9 February 2021 / Accepted: 10 February 2021 / Published: 14 February 2021
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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. View Full-Text
Keywords: human induced pluripotent stem cells (hiPSCs); drug discovery; neurodevelopmental toxicity; repurposed drugs; organoids human induced pluripotent stem cells (hiPSCs); drug discovery; neurodevelopmental toxicity; repurposed drugs; organoids
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MDPI and ACS Style

Slavin, I.; Dea, S.; Arunkumar, P.; Sodhi, N.; Montefusco, S.; Siqueira-Neto, J.; Seelke, J.; Lofstrom, M.A.; Anson, B.; Zanella, F.; Carromeu, C. Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells. Int. J. Mol. Sci. 2021, 22, 1908. https://doi.org/10.3390/ijms22041908

AMA Style

Slavin I, Dea S, Arunkumar P, Sodhi N, Montefusco S, Siqueira-Neto J, Seelke J, Lofstrom MA, Anson B, Zanella F, Carromeu C. Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells. International Journal of Molecular Sciences. 2021; 22(4):1908. https://doi.org/10.3390/ijms22041908

Chicago/Turabian Style

Slavin, Ileana; Dea, Steven; Arunkumar, Priyanka; Sodhi, Neha; Montefusco, Sandro; Siqueira-Neto, Jair; Seelke, Janet; Lofstrom, Mary A.; Anson, Blake; Zanella, Fabian; Carromeu, Cassiano. 2021. "Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in Neural Cells" Int. J. Mol. Sci. 22, no. 4: 1908. https://doi.org/10.3390/ijms22041908

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