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Updated: Nov 15, 2025
Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
Published on: June 17, 2015
Human iPSC-Derived 2D and 3D Platforms for Rapidly Assessing Developmental, Functional, and Terminal Toxicities in
Ileana Slavin1, Steven Dea1, Priyanka Arunkumar1
1StemoniX, La Jolla, CA 92037, USA.
Abstract:
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.
Insights
Drug repurposing requires careful neurotoxicity assessment. New human induced pluripotent stem cell (hiPSC)-derived neural screening platforms reveal that many antiviral compounds are toxic to developing neural tissues, emphasizing the need for stage-specific safety testing.
Area of Science:
- Neuroscience
- Toxicology
- Stem Cell Biology
Background:
- Drug repurposing accelerates therapeutic development but carries risks of off-target toxicity.
- Cellular susceptibility to drug toxicity varies significantly with developmental stage and cell type.
- Existing in vitro models may not adequately represent the diverse cellular contexts of drug exposure.
Purpose of the Study:
- To develop and validate high-throughput human induced pluripotent stem cell (hiPSC)-derived neural screening platforms for assessing neurotoxicity across different developmental stages.
- To evaluate the neurotoxicity profiles of 29 potential antiviral compounds using these novel platforms.
- To identify compounds with favorable safety profiles for further functional assessment.
Main Methods:
- Development of 2D and 3D hiPSC-derived neural cultures representing distinct neurodevelopmental stages.
- High-throughput screening of 29 therapeutic compounds for neurotoxicity across various dosages.
- Functional assessment using calcium flux assays for compounds exhibiting minimal toxicity.
Main Results:
- Significant neurotoxicity was observed for many compounds in early-stage neural cultures, with reduced toxicity in later stages.
- Only four out of 29 tested compounds demonstrated a safe viability profile across all developmental stages and dosages.
- Calcium flux assays confirmed the functional safety of the selected compounds on developing and mature neurospheroids.
Conclusions:
- Employing hiPSC-derived neural models at multiple developmental stages is crucial for comprehensive neurotoxicity profiling of therapeutics.
- The study identified a subset of compounds with a promising safety profile for potential repurposing as antivirals.
- This approach enhances the predictive value of in vitro safety assessments for drug development and repurposing efforts.
