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Molecular characterization of a toxicological tipping point during human stem cell differentiation
Citation:
Saili, K., T. Antonijevic, T. Zurlinden, I. Shah, C. Deisenroth, AND T. Knudsen. Molecular characterization of a toxicological tipping point during human stem cell differentiation. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 91(January 2020):1-13, (2020). https://doi.org/10.1016/j.reprotox.2019.10.001
Impact/Purpose:
We characterized an in vitro model of early embryonic development that identified a deleterious dose of retinoic acid relevant to human health considerations. This developmental model can be used to screen for developmental toxicants that perturb retinoic acid signaling by measuring transcriptomic changes in a selected set of gene markers and key high content imaging markers.
Description:
Embryonic development commences with the formation of three germ layers from the primitive streak during gastrulation. The endoderm layer gives rise to the gut tube, leading to development of several internal organs, including the thyroid, thymus, lungs, stomach, liver, pancreas, and intestines. We differentiated human induced pluripotent stem cells (hiPSCs) to embryonic endoderm and sought to identify a tipping point at which the developing system did not recover from perturbations caused by exposure to a known teratogen, all-trans retinoic acid (ATRA). Differentiating iPSC-derived endoderm was exposed to five concentrations of ATRA between 0.001 and 10 µM at 6h, 96h, or 192h and assessed for forkhead box A2 (FOXA2) protein expression and global gene transcript expression. A tipping point of 17±11 nM was identified where patterns of differentially expressed genes supported a shift in the developmental trajectory away from embryonic endoderm in favor of mesoderm and extraembryonic endoderm.
URLs/Downloads:
DOI: Molecular characterization of a toxicological tipping point during human stem cell differentiation
https://pubmed.ncbi.nlm.nih.gov/31600526/