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All-Trans Retinoic Acid-Mediated Transcriptomic Signatures in Human Pluripotent Stem Cells at Single-Cell Resolution
Citation:
Park, S., D. Gallegos, S. Jeffay, E. Hunter, AND B. Chorley. All-Trans Retinoic Acid-Mediated Transcriptomic Signatures in Human Pluripotent Stem Cells at Single-Cell Resolution. Environmental Mutagenesis and Genomics Society (EMGS) 54th Annual Meeting, Chicago, IL, September 09 - 13, 2023. https://doi.org/10.23645/epacomptox.24128769
Impact/Purpose:
Presentation to the Environmental Mutagenesis and Genomics Society (EMGS) 54th Annual Meeting September 2023
Description:
According to the CDC, congenital malformations affect 1 in 33 babies born in the US and are the leading cause of infant mortality. Etiological considerations are multifactorial and can include exposure to environmental chemicals. Developmental sensitivities to perturbagens are especially pronounced during embryogenesis, a period of rapid and extensive cellular proliferation and differentiation. However, characterization of chemical effects during these critical stages of embryogenesis remains under-evaluated. This necessitates utilizing physiologically relevant and mechanistically understood models that are amenable to higher-throughput chemical screening assessments.To begin addressing these needs, we examined early transcriptomic responses in human pluripotent stem cells (hPSCs) following exposure to all-trans retinoic acid (ATRA), a developmental morphogen using single-cell RNA sequencing (scRNA-seq). We treated hPSCs—in conditions that maintain pluripotency–with 0.03µM ATRA or dimethyl sulfoxide (DMSO) and collected samples at 6 and 72 hours (h) post-exposure. At 6h post ATRA-treatment, differentially expressed genes (DEGs) were ATRA-responsive (i.e., CYP26A1 and HAS2) and at 72h, we observed ATRA-associated cellular sub-types and robust DEG expression changes related to extracellular matrix interactions (focal adhesions, migration, assembly) and cardiogenesis, indicative of early ATRA-mediated stem cell differentiation. Additional analyses included ATRA-mediated inferential cell trajectory and delineation of sub-populations. Single-cell measures provide improved mechanistic and molecular insights into early normal developmental trajectory that may establish processes of maldevelopment when exposed to toxicants. These biomarkers of biological effect can further be utilized in short-term, high-throughput in vitro chemical screening models to putatively identify developmental toxicants. This abstract does not reflect EPA policy.
URLs/Downloads:
DOI: All-Trans Retinoic Acid-Mediated Transcriptomic Signatures in Human Pluripotent Stem Cells at Single-Cell Resolution
2023SEP08_EMGS_SP_FORCLEARANCE.PDF (PDF, NA pp, 16525.859 KB, about PDF)