High-throughput identification of small molecules that affect human embryonic vascular development
Name
Vazao-2017-High-throughput identification of s.pdf
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2.17 MB
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Checksum (MD5)
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Author(s)
Vazão, Helena
Rosa, Susana
Barata, Tânia
Costa, Ricardo
Pitrez, Patrícia R.
Honório, Inês
de Vries, Margreet R.
Papatsenko, Dimitri
Benedito, Rui
Saris, Daniel
Date Issued
April 2017
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Vazão, Helena et al. “High-Throughput Identification of Small Molecules That Affect Human Embryonic Vascular Development.” Proceedings of the National Academy of Sciences 114, 15 (March 2017): E3022–E3031 © 2017 National Academy of Sciences
Version
Final published version
Abstract
Birth defects, which are in part caused by exposure to environmental chemicals and pharmaceutical drugs, affect 1 in every 33 babies born in the United States each year. The current standard to screen drugs that affect embryonic development is based on prenatal animal testing; however, this approach yields low-throughput and limited mechanistic information regarding the biological pathways and potential adverse consequences in humans. To develop a screening platform for molecules that affect human embryonic development based on endothelial cells (ECs) derived from human pluripotent stem cells, we differentiated human pluripotent stem cells into embryonic ECs and induced their maturation under arterial flow conditions. These cells were then used to screen compounds that specifically affect embryonic vasculature. Using this platform, we have identified two compounds that have higher inhibitory effect in embryonic than postnatal ECs. One of them was fluphenazine (an antipsychotic), which inhibits calmodulin kinase II. The other compound was pyrrolopyrimidine (an antiinflammatory agent), which inhibits vascular endothelial growth factor receptor 2 (VEGFR2), decreases EC viability, induces an inflammatory response, and disrupts preformed vascular networks. The vascular effect of the pyrrolopyrimidine was further validated in prenatal vs. adult mouse ECs and in embryonic and adult zebrafish. We developed a platform based on human pluripotent stem cell-derived ECs for drug screening, which may open new avenues of research for the study and modulation of embryonic vasculature.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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DOI of Published Version
https://doi.org/10.1073/pnas.1617451114
