Abstract
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.
Highlights
Spina bifida aperta (SBA) is one of the most severe types of NTDs associated with herniation of neural tissue through an incompletely formed spine
To avoid transgene insertion into the host genome, we used a non-integrating Sendai virus (SeV) reprogramming approach to generate induced pluripotent stem cell (iPSC) from skin fibroblasts derived from 3 SBA fetuses and from 1 amniotic fluid derived stem cells (AFSCs) sample
We generated iPSCs from skin fibroblasts of 2 healthy adult donors and from 1 AFSC sample derived from healthy fetus as controls
Summary
Spina bifida aperta (SBA) is one of the most severe types of NTDs associated with herniation of neural tissue through an incompletely formed spine. The folate metabolic pathway plays a crucial role in nucleotide biosynthesis, proper cell proliferation and generation of methyl donors[12,13,14]. During the first-trimester of pregnancy, exposure to FA antagonists is associated with an increased risk of congenital anomalies, including NTDs15. Exposure to the folate antagonist methotrexate (MTX) induces NTDs in animal models[16]. FA, influences the proliferation and differentiation of NSCs, whereas MTX impairs cell proliferation of embryonic NSCs in animal models[18]. FOLR1 receptors are expressed on the plasmatic membrane of the human placenta[23], where they play a role in folate transport during early embryonic development. In vitro models of human NTDs to capture the pathological phenotype and reveal the mechanism of FA action are urgently needed
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