Neural stem cell quiescence and activation dynamics are regulated by feedback input from their progeny under homeostatic and regenerative conditions

Abstract

Life-long maintenance of stem cells implies that feedback mechanisms from the niche regulate their quiescence/activation dynamics. Here, in the mouse adult subventricular neural stem cell (NSC) niche, we charted a precise spatiotemporal map of functional responses in NSCs induced by multiple niche cells and used machine learning to predict NSC interactions with specific niche cell types. We revealed a feedback mechanism whereby the NSC proliferative state is directly repressed by transient amplifying cells (TAPs), their rapidly dividing progeny. NSC processes wrap around TAPs and display hotspots of Ca²⁺ activity at their points of contact, mediated by ephrin (Efn) signaling. The modulation of Efn signaling or TAP ablation altered the Ca²⁺ signature of NSCs, leading to their activation. In vivo optogenetic modulation of Ca²⁺ dynamics abrogated NSC activation and prevented niche replenishment. Thus, TAP-to-NSC feedback signaling controls stem cell quiescence and activation, providing a mechanism to maintain stem cell pools throughout life.