Focus on germ-layer markers : A human stem cell-based model for in vitro teratogenicity testing

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2020
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Zhang, Jitao David
Barrow, Paul
Ebeling, Martin
Clemann, Nicole
Kustermann, Stefan
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European Union (EU): 681002
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Reproductive Toxicology. Elsevier. 2020, 98, pp. 286-298. ISSN 0890-6238. eISSN 1873-1708. Available under: doi: 10.1016/j.reprotox.2020.10.011
Zusammenfassung

Human induced pluripotent stem cells (hiPSC) were used to develop an assay format that may deliver information on teratogenicity of drugs. A human pluripotent stem cell scorecard panel was used to monitor the expression of 96 marker genes that are indicative of the stem cell state or differentiation into the ectoderm, mesoderm and endoderm lineages. We selected a human episomal iPS cell line for the assay based on karyotype stability, initial pluripotency, differentiation capacity and overall gene expression variability. The assay is based on embryoid body formation and was developed to be simply automated. In this proof of concept study, we used eight reference compounds (valproic acid, all-trans-retinoic acid, thalidomide, methotrexate, hydroxyurea, ascorbic acid, penicillin G and ibuprofen) to test the technical performance of the assay (readout stability) in concentration-response and time-course experiments. We also found that each compound affected marker gene expression in a different way. Various forms of data analysis identified 19 out of 96 early developmental genes as potential predictive markers for teratogenicity. Machine-learning models were run to exemplify how the assay will be developed further. The preliminary results from these analyses suggest that the assay could be suitable for the pre-screening of candidate pharmaceutical compounds. The approach presented here points a way towards development of a human cell-based assay that could replace the murine EST currently used to screen for early indications of potential teratogenicity of drug candidates.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
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Teratogenicity, Gene egulation, Embryoid bodies, Scorecard, Human induced pluripotent stem cells
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ISO 690JAKLIN, Manuela, Jitao David ZHANG, Paul BARROW, Martin EBELING, Nicole CLEMANN, Marcel LEIST, Stefan KUSTERMANN, 2020. Focus on germ-layer markers : A human stem cell-based model for in vitro teratogenicity testing. In: Reproductive Toxicology. Elsevier. 2020, 98, pp. 286-298. ISSN 0890-6238. eISSN 1873-1708. Available under: doi: 10.1016/j.reprotox.2020.10.011
BibTex
@article{Jaklin2020-12Focus-51826,
  year={2020},
  doi={10.1016/j.reprotox.2020.10.011},
  title={Focus on germ-layer markers : A human stem cell-based model for in vitro teratogenicity testing},
  volume={98},
  issn={0890-6238},
  journal={Reproductive Toxicology},
  pages={286--298},
  author={Jaklin, Manuela and Zhang, Jitao David and Barrow, Paul and Ebeling, Martin and Clemann, Nicole and Leist, Marcel and Kustermann, Stefan}
}
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