PDF(Pubmed)
Abstract：
BACKGROUND: 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 birth defect. 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 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.
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.
摘要：
背景：组织融合是一种参与心脏发育的机制，虹膜,生殖器结节,神经管,胚胎发育过程中的上颚。腭架融合失败可导致腭裂(CP),常见的出生缺陷.由人体细胞构建的器官型模型提供了研究人类发育过程的机会。以前,我们的实验室开发了一个包含人类间充质和上皮祖细胞的人类腭的类器官模型，以研究化学物质对融合的影响。
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。
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。
