There is currently a debate as to whether or not a neural stem cell (NSC) exists in the adult mammalian hippocampus. Clonal colony-forming assays allow single cells to cells to be evaluated for stem cell properties: self-renewal and multipotentiality. In these in vitro assays, single cells from the subependymal zone (SEZ) of the adult lateral ventricle yield large colonies which self-renew and are multipotential, while single cells from the adult dentate gyrus (DG) produce small, unipotent, and nonself-renewing colonies. We find that multipotential and long-term self-renewing colonies can be isolated only from the early embryonic hippocampus, before the formation of the DG. No movement of progenitors from the postnatal SEZ to the newly forming DG subgranular zone is detected and adult DG colonies in vitro originate from the embryonic hippocampal primordium. These data support a model where embryonic hippocampal NSCs change their properties as the organism ages. When adult DG spheres are cocultured with embryonic brain slices, self-renewal (but not multipotentiality) is restored and maintained for several passages off of slices. Adult clonal DG spheres grown on embryonic brain slices or transplanted into brains of neonatal mice do not give rise to neurons. Neurons arise from separate, small clones that are approximately 10 times more frequent than sphere colonies in vitro and may be responsible for maintaining neurogenesis in the adult in vivo. We propose that there are separate glial and neuronal clones in the adult hippocampus, with glial progenitors being the most proliferative in culture.

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