Introduction: Quiescent tumor-initiating with neural stem cell-like properties are resistant to therapy and enable tumor recurrence. As such, quiescent tumor stem cells are increasingly targeted by novel anti-tumor therapies. Quiescent neural stem cells (NSCs) are extremely similar to tumor stem cells and may be targeted by these therapies. 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 for 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 without increasing 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, although surviving NSCs remain functional and responsive to proliferative stimuli. Primitive ESC-derived NSC also cannot engraft into the 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.
Patient Care: Awareness of the fragile nature of the adult neurogenic niche can facilitate efforts to better define differences between quiescent neural stem cells and quiescent tumor stem cells. Selective therapies that spare adult neurogenesis may enhance long-term cognitive outcomes following novel anti-tumor therapies.
Learning Objectives: Adult quiescent neural stem cells are important for cognition but are a non-renewable resource. Loss of quiescent neural stem cells following novel stem-cell targeted anti-tumor therapies will likely be permanent raising the potential for permanent cognitive sequelae.