Human pluripotent stem cell-derived neural constructs for predicting neural toxicity.
Proc Natl Acad Sci U S A
; 112(40): 12516-21, 2015 Oct 06.
Article
em En
| MEDLINE
| ID: mdl-26392547
ABSTRACT
Human pluripotent stem cell-based in vitro models that reflect human physiology have the potential to reduce the number of drug failures in clinical trials and offer a cost-effective approach for assessing chemical safety. Here, human embryonic stem (ES) cell-derived neural progenitor cells, endothelial cells, mesenchymal stem cells, and microglia/macrophage precursors were combined on chemically defined polyethylene glycol hydrogels and cultured in serum-free medium to model cellular interactions within the developing brain. The precursors self-assembled into 3D neural constructs with diverse neuronal and glial populations, interconnected vascular networks, and ramified microglia. Replicate constructs were reproducible by RNA sequencing (RNA-Seq) and expressed neurogenesis, vasculature development, and microglia genes. Linear support vector machines were used to construct a predictive model from RNA-Seq data for 240 neural constructs treated with 34 toxic and 26 nontoxic chemicals. The predictive model was evaluated using two standard hold-out testing methods:
a nearly unbiased leave-one-out cross-validation for the 60 training compounds and an unbiased blinded trial using a single hold-out set of 10 additional chemicals. The linear support vector produced an estimate for future data of 0.91 in the cross-validation experiment and correctly classified 9 of 10 chemicals in the blinded trial.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
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Células-Tronco Pluripotentes
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Células-Tronco Embrionárias
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Células-Tronco Neurais
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article