THREE-DIMENSIONAL MOUSE STEM CELL-DERIVED GASTRULOIDS: AN IN VITRO APPROACH TO STUDY THE IMPACT OF TERATOGENS DURING GASTRULATION
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2021
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Teratogens are harmful chemical, physical or biological environmental exposure to childbearing and pregnant women that can increase the incidences of birth defects. To minimize the incidences of birth defects, it is important to identify teratogenic agents. However, there is no easy and reliable test to screen for teratogenic effects of substances. Epidemiologic studies in human are only retrospective, relying on hundreds of tragic incidences that had already happened to attain statistically sound conclusions, whereas experimentations using live animals are costly, laborious and associated with ethical issues. To compensate for these caveats of in vivo studies, in vitro teratogen tests using pluripotent stem cells are explored. Pluripotent stem cells can self-renew in culture indefinitely while retaining the developmental ability of early embryos. They can be induced to differentiate in vitro to mimic key aspects of embryogenesis, which may be used to evaluate the adverse effects of teratogenic exposures. The goal of my dissertation project is to validate one such stem cell-based in vitro embryogenesis model and apply it to elucidate the molecular mechanisms of some known teratogenic agents. First, we demonstrated that the morphogenesis and gene expression profile of the 3D stem cell model, known as the P19C5 gastruloid, are regulated by the same molecular machineries that function during early stages of normal embryogenesis, when body axis elongation and patterning take place. Second, we identified the molecular mechanisms, by which anti-epileptic medication, valproic acid, exerts its teratogenic effects through enhanced activation of retinoic acid signaling. Third, we revealed that methoxyacetic acid, the major metabolite of industrial products, including plasticizers and organic solvents, also enhance retinoic acid signaling to cause its adverse effects. Based on my dissertation project, we expect P19C5 gastruloid can serve as an effective in vitro model to assess the teratogenic potential of environmental exposures that may cause birth defects and explain the mechanisms of teratogenic agents to reduce the incidences of tragic birth defects
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Developmental biology, Gastruloid, In vitro, Methoxyacetic Acid, Stem Cells, Teratogens, Valproic Acid
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116 pages
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