STEM-06ADULT NEURAL STEM CELLS ARE IRREPLACEABLE

Abstract

BACKGROUND: Quiescent tumor-initiating with neural stem cell-like properties are resistant to antiproliferative therapy, enabling tumor recurrence. As such, increasing attention is focused on quiescent tumor stem cells. Quiescent neural stem cells (NSCs) share many features with tumor stem cells and may be ablated by suched targetted therapies, yielding adverse cognitive sequelae. The capacity of the quiescent NSC niche to recover following ablation remains unknown. METHODS: Nestin-creERT2::diphtheria toxin reporter (DTR) mice were induced to express DTR on NSCs with 3 days 150mg/kg i.p. tamoxifen. Ablation and control mice were treated with 100ug/kg diphtheria toxin DT or vehicle, respectively. Proliferative cells were labeled with BrdU prior to sacrifice. For cell replacement experiments, embryonic stem cell (ESC)-derived NSCs were stereotactically implanted into the dentate gyrus and lateral ventricle. RESULTS: Ablation caused 50-80% reduction of quiescent NSCs and BrdU+ within 10 days. NSC loss persisted at least 2 months, and was accompanied by 48% loss of neurogenesis at 2 months (p < 0.01), suggesting inability of the partially vacated neurogenic niche to be repopulated over time by surviving NSCs. ESC-derived NSCs increased proliferation of endogenous NSCs though only modestly impacted the quiescent NSC pool size. Implanted NSCs also differentiated into neurons with appropriate morphology and projections but failed to engraft long term into the quiescent NSC niche. CONCLUSIONS: We demonstrate for the first time that adult NSCs are unable to repopulate the quiescent NSC niche after partial ablation of quiescent NSCs, even though surviving NSCs remain functional and responsive to proliferative stimuli. Primitive ESC-derived NSC also appear unable to engraft into the quiescent vacated niche. These findings suggest that loss of quiescent NSCs irreversibly decreases niche size. Given the importance of neurogenesis for cognition and memory, the potentially irreversible impacts of novel stem cell-targeted antitumor therapies on quiescent NSC pool size should be carefully evaluated.