Human pluripotent stem cell-derived neural constructs for predicting neural toxicity
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Significance: Stem cell biology, tissue engineering, bioinformatics, and machine learning were combined to implement an in vitro human cellular model for developmental neurotoxicity screening. Human pluripotent stem cell-derived neural tissue constructs with vascular networks and microglia were produced with high sample uniformity by combining precursor cells on synthetic hydrogels using standard culture techniques. Machine learning was used to build a predictive model from changes in global gene expression for neural constructs exposed to 60 toxic and nontoxic training chemicals. The model correctly classified 9 of 10 additional chemicals in a blinded trial. This combined strategy demonstrates the value of human cell-based assays for predictive toxicology and should be useful for both drug and chemical safety assessment.
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Schwartz et al. (2015) generated highly uniform hPSC-derived neural constructs on PEG hydrogels, supporting controlled pluripotency exit, neural induction, and toxicity-responsive neurogenesis.
“Schwartz et al. (2015) generated highly uniform hPSC-derived neural constructs on PEG hydrogels, supporting controlled pluripotency exit, neural induction, and toxicity-responsive neurogenesis.”
From Challenges and solutions in transitioning to animal-free standards: a comprehensive analysis of components in human cell-based developmental neurotoxicity assays (2026) · cites this paper as Schwartz et al. (2015)
The Discussion reports high sample uniformity and self-assembly on PEG hydrogels; the Results show neural differentiation and expression of neurogenesis genes. But the Results say already-derived neural progenitors were seeded on the hydrogels, not that the hydrogels controlled pluripotency exit or neural induction. The toxicity experiments measured changes in global gene expression, without establishing a specifically toxicity-responsive neurogenesis process. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNeurons from familial and sporadic Alzheimer's patients show enlarged early endosomes, phosphorylated tau, and increased Aβ peptides and oligomers.
“Neurons derived from familial as well as sporadic Alzheimer’s patient cells show enlarged early endosomes100, phosphorylated tau100, and increased production of Aβ peptides100 and oligomers101.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [101]
In a blinded test, nine out of ten tested chemicals were correctly identified as toxic or nontoxic by a machine-learning algorithm built from RNA-seq data of neural organoids.
“In a blinded test, nine out of ten tested chemicals were correctly identified as toxic or nontoxic;”
From Towards organoid culture without Matrigel (2021) · cites this paper as [169]
Schwartz et al. used toxic and non-toxic compounds to treat 3D-cultured human pluripotent stem cell-derived neural cells, RNA-Seq, and SVM to classify chemicals by toxicity, gaining average AUC of 0.91.
“Schwartz et al. used both toxic and non-toxic compounds to treat 3D-cultured human pluripotent stem cell-derived neural cells, then used RNA-Seq to determine the whole genome expression profile, and then used SVM to classify the chemicals according to their toxicity. The scheme gained an average AUC value of 0.91 [132].”
From Machine Learning Based Toxicity Prediction: From Chemical Structural Description to Transcriptome Analysis (2018) · cites this paper as [132]
Schwartz et al. (2015) successfully seeded iPSC macrophages into 3D iPSC-neuronal structures for toxicity testing, but did not characterize the resulting cells extensively.
“Schwartz et al. (2015) recently successfully seeded iPSC macrophages into 3D iPSC-neuronal structures for toxicity testing, but did not characterize the resulting cells extensively.”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Schwartz et al., 2015
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“To begin investigating lineage-specific transcriptomic features at single-cell resolution, we performed a cohort of scRNA-seq experiments profiling snapshots of lineagespecific progenitor cells differentiated from H1 human ES cells using our established differentiation protocols, all adapted to chemically-defined cult…”
MethodInfluentialSelf-citationInterconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies
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Towards organoid culture without Matrigel
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The promises and challenges of human brain organoids as models of neuropsychiatric disease
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A statistical approach for identifying differential distributions in single-cell RNA-seq experiments
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CRISPR-based functional genomics for neurological disease
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Complex Tissue and Disease Modeling using hiPSCs
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Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion
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- Authors
- Schwartz, M. P., Hou, Z., Propson, N. E., Zhang, J., Engstrom, C. J., Costa, V. S., Jiang, P., Nguyen, B. K., Bolin, J. M., Daly, W., Wang, Y., Stewart, R., Page, C. D., Murphy, W. L., & Thomson, J. A.
- Affiliations
- University of Wisconsin–Madison (US)
- Morgridge Institute for Research (US)
- Center for Research in Advanced Computing Systems, Institute for Systems and Computer Engineering, Technology and Science, and Department of Computer Science, Faculty of Sciences, University of Porto, Porto 4169-007, Portugal;
- University of Wisconsin System (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-09-21
- Volume
- 112
- Issue
- 40
- Pages
- 12516-12521
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4603492
- OpenAlex
- W1843099843
- Cited by
- 325
- References
- 88
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 24 · 2023: 17 · 2022: 21 · 2021: 28 · 2020: 36 · 2019: 40 · 2018: 52 · 2017: 43 · 2016: 36 · 2015: 2 · 2014: 1
- FWCI
- 19.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Funders
- HHS | National Institutes of Health (NIH 1UH2TR000506-01, 3UH2TR000506-02S1, 4UH3TR000506-03, R21EB016381-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- human pluripotent stem cells, poly(ethylene glycol) hydrogels, microglia, vascular system, neurogenesis, support vector machine classification, chemical safety assessment, in vitro toxicity models, mesenchymal stem cells, endothelial cells
- MeSH terms
- Brain, Cell Communication, Cell Differentiation, Cells, Cultured, Humans, Macrophages, Models, Biological, Polyethylene Glycols, Xenobiotics, Culture Media, Serum-Free, Microglia, Gene Expression Regulation, Developmental, Hydrogels, Tissue Engineering, Pluripotent Stem Cells, Endothelial Cells, Embryonic Stem Cells, Neurogenesis, Neural Stem Cells, Mesenchymal Stem Cells, Support Vector Machine, Gene Ontology
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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