Sahakyan Vardine, Duelen Robin, Tam Wai Long, Roberts Scott J, Grosemans Hanne, Berckmans Pieter, Ceccarelli Gabriele, Pelizzo Gloria, Broccoli Vania, Deprest Jan, Luyten Frank P, Verfaillie Catherine M, Sampaolesi Maurilio
Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology Unit, Stem Cell Institute, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center, and Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.
Sci Rep. 2018 Feb 13;8(1):2942. doi: 10.1038/s41598-018-21103-8.
Neural tube defects (NTDs) are severe congenital abnormalities, caused by failed closure of neural tube during early embryonic development. Periconceptional folic acid (FA) supplementation greatly reduces the risk of NTDs. However, the molecular mechanisms behind NTDs and the preventive role of FA remain unclear. Here, we use human induced pluripotent stem cells (iPSCs) derived from fetuses with spina bifida aperta (SBA) to study the pathophysiology of NTDs and explore the effects of FA exposure. We report that FA exposure in SBA model is necessary for the proper formation and maturation of neural tube structures and robust differentiation of mesodermal derivatives. Additionally, we show that the folate antagonist methotrexate dramatically affects the formation of neural tube structures and FA partially reverts this aberrant phenotype. In conclusion, we present a novel model for human NTDs and provide evidence that it is a powerful tool to investigate the molecular mechanisms underlying NTDs, test drugs for therapeutic approaches.
神经管缺陷（NTDs）是严重的先天性异常，由胚胎早期发育过程中神经管闭合失败引起。孕前补充叶酸（FA）可大大降低NTDs的风险。然而，NTDs背后的分子机制以及FA的预防作用仍不清楚。在这里，我们使用来自开放性脊柱裂（SBA）胎儿的人诱导多能干细胞（iPSC）来研究NTDs的病理生理学，并探索FA暴露的影响。我们报告说，在SBA模型中暴露于FA对于神经管结构的正常形成和成熟以及中胚层衍生物的强大分化是必要的。此外，我们表明叶酸拮抗剂甲氨蝶呤会显著影响神经管结构的形成，而FA部分逆转了这种异常表型。总之，我们提出了一种新的人类NTDs模型，并提供证据表明它是研究NTDs潜在分子机制、测试治疗方法药物的有力工具。
