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 contact point 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.
CONCLUSIONS: This sensitive human three-cell-type organotypic model accurately evaluates chemicals for cleft palate teratogenicity.
方法:这里,我们开发了一个能代表胚胎腭的类器官模型,包括三种细胞类型:间充质,内皮,和上皮细胞。我们通过类器官之间接触点的上皮细胞减少来测量融合,并比较了CP致畸剂对融合和毒性的影响。我们在新模型中进一步测试了其他可疑的致畸剂。
结果:我们发现三细胞型模型对丙戊酸和FGF抑制剂的融合抑制更敏感,BMP,和TGFβRI/II。在这个新模型中,我们测试了其他可疑的CP致畸剂,发现诺考达唑,托吡酯,和Y27632在不诱导毒性的浓度下抑制融合。
结论:这种敏感的人类三细胞型器官模型可以准确地评估化学物质对腭裂的致畸作用。