[The generation of neural stem cells: induction of neural stem cells from embryonic stem (ES) cells]

Abstract

Neural stem cells are considered the ultimate lineage precursors to all neurons and glia. Despite the significance of neural stem cells in the mammalian brain development, their ontogenesis remains unclear. We have established a colony-forming embryonic stem (ES) sphere assay, where ES cells were cultured in serum-free media in the presence of leukemia inhibitory factor (LIF) to form floating spheres. LIF-dependent ES cell-derived sphere cells showed self-renewal and neural multipotentiality, cardinal features of the neural stem cell, but retained some non-neural properties and broader potential. We dabbed the cells in the ES cell-derived sphere of primitive neural stem cells. LIF-dependent sphere-forming cells were also present in the epiblast of embryonic day 5.5-7.5 mouse embryos. The generation of the in vivo primitive neural stem cell was independent of Notch signaling but the activation of Notch pathway was necessary for the transition from the primitive neural stem cell to the neural stem cell. We propose that the neural stem cell originates from the pluripotent inner cell mass/epiblast cell via the primitive neural stem cell stage under the control of Notch signaling.