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A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
Published on: May 12, 2017
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High-throughput identification of small molecules that affect human embryonic vascular development
Helena Vazão1, Susana Rosa1, Tânia Barata1,2
1Center for Neurosciences and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal.
Summary
Researchers developed a human stem cell-based platform to screen drugs affecting embryonic development. This new method identified compounds impacting embryonic vasculature, offering a more effective alternative to animal testing for drug safety.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Toxicology
Background:
- Birth defects affect 1 in 33 US infants, often due to environmental chemical and drug exposure.
- Current prenatal drug screening relies on low-throughput animal models, lacking human-specific mechanistic insights.
- Understanding human embryonic development and drug effects is crucial for preventing birth defects.
Purpose of the Study:
- To develop a high-throughput screening platform for molecules impacting human embryonic development.
- To utilize human pluripotent stem cell-derived endothelial cells (ECs) for drug screening.
- To identify compounds affecting embryonic vasculature and their mechanisms of action.
Main Methods:
- Differentiated human pluripotent stem cells into embryonic ECs and matured them under arterial flow.
- Screened compounds for effects on embryonic vasculature using the developed EC platform.
- Validated findings using in vitro models (mouse ECs) and in vivo models (zebrafish).
Main Results:
- Identified two compounds with higher inhibitory effects on embryonic ECs than postnatal ECs.
- Fluphenazine (antipsychotic) was found to inhibit calmodulin kinase II.
- Pyrrolopyrimidine (anti-inflammatory) inhibited VEGFR2, decreased EC viability, induced inflammation, and disrupted vascular networks.
Conclusions:
- A novel screening platform using human pluripotent stem cell-derived ECs was established for drug discovery.
- This platform enables the study and modulation of embryonic vasculature, improving drug safety assessment.
- The findings provide new avenues for understanding and mitigating drug-induced developmental toxicity.
