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High-throughput identification of small molecules that affect human embryonic vascular development

Vazão, Helena; Rosa, Susana; Barata, Tânia; Costa, Ricardo; Pitrez, Patrícia R; Honório, Inês; de Vries, Margreet R; Papatsenko, Dimitri; Benedito, Rui and Saris, Daniel, et al. (2017) In Proceedings of the National Academy of Sciences of the United States of America 114(15). p.3022-3031
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... (More)

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.

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keywords
Journal Article
in
Proceedings of the National Academy of Sciences of the United States of America
volume
114
issue
15
pages
3022 - 3031
publisher
National Acad Sciences
ISSN
1091-6490
DOI
10.1073/pnas.1617451114
language
English
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no
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8c6d324c-453b-4f75-b31a-acdc1180851f
date added to LUP
2017-10-02 17:40:09
date last changed
2017-12-04 16:13:31
@article{8c6d324c-453b-4f75-b31a-acdc1180851f,
  abstract     = {<p>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.</p>},
  author       = {Vazão, Helena and Rosa, Susana and Barata, Tânia and Costa, Ricardo and Pitrez, Patrícia R and Honório, Inês and de Vries, Margreet R and Papatsenko, Dimitri and Benedito, Rui and Saris, Daniel and Khademhosseini, Ali and Quax, Paul H A and Pereira, Carlos F and Mercader, Nadia and Fernandes, Hugo and Ferreira, Lino},
  issn         = {1091-6490},
  keyword      = {Journal Article},
  language     = {eng},
  month        = {04},
  number       = {15},
  pages        = {3022--3031},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {High-throughput identification of small molecules that affect human embryonic vascular development},
  url          = {http://dx.doi.org/10.1073/pnas.1617451114},
  volume       = {114},
  year         = {2017},
}