Brain-derived neurotrophic factor stimulates the neural differentiation of human umbilical cord blood-derived mesenchymal stem cells and survival of differentiated cells through MAPK/ERK and PI3K/Akt-dependent signaling pathways

Abstract

Brain-derived neurotrophic factor (BDNF) plays an important role in the differentiation, development, and survival of neural stem cells. In this study, we analyzed its effects on the stimulation of human umbilical cord blood-derived mesenchymal stem cells in terms of their potential to differentiate into neuron-like cells, their survival characteristics, and the molecular mechanisms involved. The treatment of cells with neural induction medium (NIM) and BDNF generated more cells that were neuron-like and produced stronger expression of neural-lineage markers than cells treated with NIM and without BDNF. Raf-1 and ERK phosphorylation and p35 expression levels increased significantly in cells treated with both NIM and BDNF. This treatment also effectively blocked cell death following neural induction and increased Akt phosphorylation and Bcl2 expression compared with cells treated with NIM without BDNF. Inhibition of ERKs inhibited the BDNF-stimulated up-regulation of p35 and Bcl2. In addition, the inhibition of PI3K abrogated Akt phosphorylation and Bcl2 expression, but not p35 expression. Thus, MAPK/ERK-dependent p35 up-regulation and MAPK/ERK-dependent and PI3K/Akt-dependent Bcl2 up-regulation contribute to BDNF-stimulated neural differentiation and to the survival of differentiated cells.