A novel hiPSC-derived system for hematoendothelial and myeloid blood toxicity screens identifies compounds promoting and inhibiting endothelial-to-hematopoietic transition

Irina Elcheva, Mechelle Sneed, Scott Frazee, Zhenqiu Liu, Junjia Zhu, Tyler Wood, Sara Hendrickson, Chuck Oehler, Brad Garcia, Vladimir Spiegelman

Research output: Contribution to journalArticle

Abstract

The exposure to toxic environmental and pharmaceutical substances can pose a long-term risk to human's health. In this study, we sought to investigate the potential of our recently developed method for induction of myeloid hematoendothelial and blood cells by overexpression of two transcription factors, GATA2 and ETV2, in human induced pluripotent stem cells (hiPSCs) for toxicity screening. For the primary screen in a high-throughput format, we selected twenty-two chemicals with various degrees of cytotoxicity available from the NIEHS National Toxicology Program (Tox21). The compounds were applied during the endothelial-to-hematopoietic transition and to differentiated myeloid progenitors growing in suspension. The system was capable of identifying compounds with both inhibitory and favorable effects on hematopoietic network, changes in expression of hematopoietic markers, and mitochondrial and cytotoxicity. The findings were confirmed and further investigated by secondary screens, colony forming cell assay, and gene expression profiling. The hematoendothelial toxicity of 5-fluorouracil, berberine chloride, and benzo(a)pyrene is characterized by the inhibition of cell division and a shift of hematopoietic programming to non-hemogenic endothelial and mesenchymal fates. This study demonstrates the feasibility of transcription factor (TF)-based differentiation systems to monitor endothelial and hematotoxicity and serves as an informative platform for screening myelosuppressive or stimulatory drugs and mechanistic studies of their action.

Original languageEnglish (US)
Article number104622
JournalToxicology in Vitro
Volume61
DOIs
StatePublished - Dec 1 2019

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Induced Pluripotent Stem Cells
Cytotoxicity
Toxicity
GATA2 Transcription Factor
Screening
National Institute of Environmental Health Sciences (U.S.)
Blood
Cells
Berberine
Hazardous Substances
Poisons
Benzo(a)pyrene
Feasibility Studies
Gene Expression Profiling
Myeloid Cells
Stem cells
Gene expression
Fluorouracil
Pharmaceutical Preparations
Cell Division

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Elcheva, Irina ; Sneed, Mechelle ; Frazee, Scott ; Liu, Zhenqiu ; Zhu, Junjia ; Wood, Tyler ; Hendrickson, Sara ; Oehler, Chuck ; Garcia, Brad ; Spiegelman, Vladimir. / A novel hiPSC-derived system for hematoendothelial and myeloid blood toxicity screens identifies compounds promoting and inhibiting endothelial-to-hematopoietic transition. In: Toxicology in Vitro. 2019 ; Vol. 61.
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A novel hiPSC-derived system for hematoendothelial and myeloid blood toxicity screens identifies compounds promoting and inhibiting endothelial-to-hematopoietic transition. / Elcheva, Irina; Sneed, Mechelle; Frazee, Scott; Liu, Zhenqiu; Zhu, Junjia; Wood, Tyler; Hendrickson, Sara; Oehler, Chuck; Garcia, Brad; Spiegelman, Vladimir.

In: Toxicology in Vitro, Vol. 61, 104622, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Zhu, Junjia

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AU - Hendrickson, Sara

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AU - Garcia, Brad

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