Effectiveness of Multivitamins vs Folic Acid on Prevention of Neural Tube Defects in Mouse Genetic Models and Human Organoids

Maternal consumption of folic acid (FA)-containing multivitamins/minerals (MVM) are recommended to reduce the risk for neural tube defects (NTDs). However, comparison between MVM supplementation and FA alone relative to NTD risk and possible mechanisms remain unclear. The studies demonstrate MVM can decrease NTD incidence in mouse genetic models with FA-resistant or FA-detrimental responses. To evaluate cellular and metabolic impacts, human iPSC-derived neuroectoderm organoids are generated with an elliptical shape resembling the human neural tube and cranial to upper spinal identity. Upon pharmacological or genetic disruption, both MVM or FA alone can normalize abnormal apical F-actin, lumen size, and premature neuronal differentiation. However, FA alone enhances DNA synthesis and shortens the cell division rate, while MVM maintains these parameters at control levels. High-performance liquid chromatography (HPLC) analysis of mouse embryos and human organoids indicates FA causes more variation of the nucleotide pool, whereas MVM maintains homeostasis. Thymine is reduced in FA alone and increased in MVM and thymine/thymidine supplementation can ameliorate FA-induced hyperactivation of cell division. The in vivo cellular and phenotypic data in human organoids and mice show the effectiveness of MVM supplementation, that in some cases surpasses FA alone, in maintaining cellular homeostasis and preventing NTD.