Quiescent Oct4(+) Neural Stem Cells (NSCs) Repopulate Ablated Glial Fibrillary Acidic Protein(+) NSCs in the Adult Mouse Brain.
Stem Cells. 2017 Jul 21;:
Authors: Reeve RL, Yammine SZ, Morshead CM, van der Kooy D
Adult primitive neural stem cells (pNSCs) are a rare population of glial fibrillary acidic protein (GFAP)(-) Oct4(+) cells in the mouse forebrain subependymal zone bordering the lateral ventricles that give rise to clonal neurospheres in leukemia inhibitory factor in vitro. pNSC neurospheres can be passaged to self-renew or give rise to GFAP(+) NSCs that form neurospheres in epidermal growth factor and fibroblast growth factor 2, which we collectively refer to as definitive NSCs (dNSCs). Label retention experiments using doxycycline-inducible histone-2B (H2B)-green fluorescent protein (GFP) mice and several chase periods of up to 1 year quantified the adult pNSC cell cycle time as 3-5 months. We hypothesized that while pNSCs are not very proliferative at baseline, they may exist as a reserve pool of NSCs in case of injury. To test this function of pNSCs, we obtained conditional Oct4 knockout mice, Oct4(fl/fl) ;Sox1(Cre) (Oct4(CKO) ), which do not yield adult pNSC-derived neurospheres. When we ablated the progeny of pNSCs, namely all GFAP(+) dNSCs, in these Oct4(CKO) mice, we found that dNSCs did not recover as they do in wild-type mice, suggesting that pNSCs are necessary for dNSC repopulation. Returning to the H2B-GFP mice, we observed that the cytosine β-d-arabinofuranoside ablation of proliferating cells including dNSCs-induced quiescent pNSCs to proliferate and significantly dilute their H2B-GFP label. In conclusion, we demonstrate that pNSCs are the most quiescent stem cells in the adult brain reported to date and that their lineage position upstream of GFAP(+) dNSCs allows them to repopulate a depleted neural lineage. Stem Cells 2017.
PMID: 28733998 [PubMed - as supplied by publisher]