Human pluripotent stem cell-derived neural constructs for predicting neural toxicity.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Schwartz, MP; Hou, Z; Propson, NE; Zhang, J; Engstrom, CJ; Santos Costa, V; Jiang, P; Nguyen, BK; Bolin, JM; Daly, W; Wang, Y; Stewart, R; Page, CD; Murphy, WL; Thomson, JA

Published Date

  • October 6, 2015

Published In

Volume / Issue

  • 112 / 40

Start / End Page

  • 12516 - 12521

PubMed ID

  • 26392547

Pubmed Central ID

  • 26392547

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1516645112

Language

  • eng

Conference Location

  • United States