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An Improved Multicellular Human Organoid Model for the Study of Chemical Effects on Palate Fusion

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  • Overview
In this study we created a human stem cell organotypic model of the palate with mesenchymal, endothelial and epithelial cells and tested various suspect teratogenic chemicals on fusion of the palate organoids.  AbstractBackground: Tissue fusion is a mechanism involved in the development of the heart, iris, genital tubercle, neural tube, and palate during embryogenesis. Failed fusion of the palatal shelves could result in cleft palate (CP), a common birthdefect. Organotypic models constructed of human cells offer an opportunity to investigate developmental processes in the human. Previously, our laboratory developed an organoid model of the human palate that contains human mesenchyme and epithelial progenitor cells to study the effects of chemicals on fusion.Methods: Here, we developed an organoid model more representative of the embryonic palate that includes three cell types: mesenchyme, endothelial, and epithelial cells. We measured fusion by a decrease in epithelial cells at the contactpoint between the organoids and compared the effects of CP teratogens on fusion and toxicity in the previous and current organoid models. We further tested additional suspect teratogens in our new model.Results: We found that the three-cell-type model is more sensitive to fusion inhibition by valproic acid and inhibitors of FGF, BMP, and TGFβRI/II. In this new model, we tested other suspect CP teratogens and found that nocodazole, topiramate, and Y27632 inhibit fusion at concentrations that do not induce toxicity.Conclusion: This sensitive human three-cell-type organotypic model accuratelyevaluates chemicals for cleft palate teratogenicity.

Impact/Purpose

Cleft palate and other orofacial clefts are one of the most common birth defects, affecting 1 in 700 births worldwide. The study of the etiology of cleft palate in the human is difficult to study. Study has been restricted to in vivo studies in rodents or in vitro organ culture of rodent palates. Culture of spheroids and heterotypic organoids generated from human stem cells allows us to model palatal fusion in humans with a 3D human palate model, and test suspect cleft palate teratogens on fusion of these palate organoids.

Citation

Wolf, C. An Improved Multicellular Human Organoid Model for the Study of Chemical Effects on Palate Fusion. Society of Birth Defects Research and Prevention Annual Meeting, Pittsburgh, PA, June 22 - 26, 2024.
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Last updated on November 20, 2024
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