Both Wnt/β-catenin and ERK5 signaling pathways are involved in BDNF-induced differentiation of pluripotent stem cells into neural stem cells.

Although brain-derived neurotrophic factor (BDNF) induces the differentiation of induced pluripotent stem cells (iPSCs) into neural stem cells (NSCs), its exact mechanism remains unelucidated. Wnt/β-catenin and ERK5 are two important signalling pathways of the Wnt and MAPK signalling cascades and are speculated to be closely related to the differentiation of cells. In this study, we reported the role of the Wnt/β-catenin and ERK5 signalling pathways on the BDNF-induced differentiation of iPSCs into NSCs. We examined the expression of β-catenin and p-ERK5 using small interfering RNA (siRNA)-induced silencing of β-catenin and ERK genes. We found that BDNF significantly improved the efficiency of iPSC differentiation and that the expression of β-catenin and p-ERK5 in the BDNF culture medium was significantly upregulated. Furthermore, we found that the expression of the β-catenin component was downregulated by siRNA-β-catenin, and the expression of the p-ERK5 component was downregulated by siRNA-ERK5. Flow cytometry showed that the differentiation rate of iPSCs was also significantly decreased by RNA interference. The results suggested that the Wnt/β-catenin and ERK5 signalling pathways are activated in the process of BDNF-induced iPSC differentiation. Interestingly, our study showed that siRNA-ERK5 not only inhibits the activity of the ERK5 signalling pathway but also partially controls the activity of the Wnt/β-catenin signalling pathway. The results suggested that the Wnt/β-catenin and ERK5 signalling pathways are not independently involved in the process of BDNF-induced iPSC differentiation. Our study showed that BDNF promotes the differentiation of iPSCs into NSCs by activating the Wnt/β-catenin and ERK5 signalling pathways, and an interconnected relationship may exist between the Wnt/β-catenin and ERK5 signalling pathways.