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

Publication ,  Journal Article
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 ...
Published in: Proc Natl Acad Sci U S A
October 6, 2015

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 6, 2015

Volume

112

Issue

40

Start / End Page

12516 / 12521

Location

United States

Related Subject Headings

  • Xenobiotics
  • Tissue Engineering
  • Support Vector Machine
  • Polyethylene Glycols
  • Pluripotent Stem Cells
  • Neurogenesis
  • Neural Stem Cells
  • Models, Biological
  • Microglia
  • Mesenchymal Stem Cells
 

Citation

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Schwartz, M. P., Hou, Z., Propson, N. E., Zhang, J., Engstrom, C. J., Santos Costa, V., … Thomson, J. A. (2015). Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc Natl Acad Sci U S A, 112(40), 12516–12521. https://doi.org/10.1073/pnas.1516645112
Schwartz, Michael P., Zhonggang Hou, Nicholas E. Propson, Jue Zhang, Collin J. Engstrom, Vitor Santos Costa, Peng Jiang, et al. “Human pluripotent stem cell-derived neural constructs for predicting neural toxicity.Proc Natl Acad Sci U S A 112, no. 40 (October 6, 2015): 12516–21. https://doi.org/10.1073/pnas.1516645112.
Schwartz MP, Hou Z, Propson NE, Zhang J, Engstrom CJ, Santos Costa V, et al. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12516–21.
Schwartz, Michael P., et al. “Human pluripotent stem cell-derived neural constructs for predicting neural toxicity.Proc Natl Acad Sci U S A, vol. 112, no. 40, Oct. 2015, pp. 12516–21. Pubmed, doi:10.1073/pnas.1516645112.
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. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12516–12521.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 6, 2015

Volume

112

Issue

40

Start / End Page

12516 / 12521

Location

United States

Related Subject Headings

  • Xenobiotics
  • Tissue Engineering
  • Support Vector Machine
  • Polyethylene Glycols
  • Pluripotent Stem Cells
  • Neurogenesis
  • Neural Stem Cells
  • Models, Biological
  • Microglia
  • Mesenchymal Stem Cells