Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

Significance Adult mammalian tissues contain stem cells that contribute to tissue homeostasis and regeneration, with potential therapeutic applications. Specialized niches regulate their fate. Here we evaluated quantitatively how the subependymal zone niche regulates neural stem cell (NSC) number in the adult mouse brain. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Using the Ki67-iresCreER mouse model, we found that dividing stem cells have long-term self-renewal potential. We propose a model where the fate of NSCs is coupled to their density within a closed niche. Our results suggest a new mechanism for regulating adult stem cell number, which might be deregulated in brain malignancies and in aging. The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.

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