Selenium promotes neural development through the regulation of GPX4 and SEPP1 in an iPSC-derived neuronal model.

Selenium (Se) is incorporated into selenoproteins in the form of selenocysteine, which has biological functions associated with neural development. Unfortunately, the specific roles and mechanisms of selenoproteins at different stages of neuronal development are still unclear. Therefore, in this study, we successfully established a neuronal model derived from induced pluripotent stem cells (iPSC-iNeuron) and used Se nanoparticles (SeNPs@LNT) with high bioavailability to intervene at different stages of neural development in iPSC-iNeuron model. Interestingly, our results showed that SeNPs@LNT could not only accelerate the proliferation of neural progenitor cells (NPCs) by upregulating glutathione peroxidase 4 (GPX4) during the NPC stage, but also can promote neuronal differentiation by increasing selenoprotein P (SEPP1) during the neuronal stage, resulting in efficient and rapid neural development. In addition, further mechanistic studies showed that SeNPs@LNT can regulate selenoproteins by activating the PI3K/Akt/Nrf2 signaling pathway, thereby affecting neuronal development. Notably, Further analysis of ASD patients in National Center for Biotechnology Information single-cell RNA-seq datasets also revealed significantly lower GPX4 expression within NRGN-expressing neurons in ASD patients, and GO enrichment analysis of genes in NRGN-expressing neurons from ASD patients showed that the downregulation of selenoproteins due to aberrant selenoprotein synthesis may be closely associated with decreased ATP synthesis resulting from abnormal mitochondrial and respiratory chain signaling pathways. Taken together, this study provides evidence that SeNPs@LNT exerts a beneficial effect on early neural development through the regulation of selenoproteins.