Adult Neural Stem Cells Are Alerted by Systemic Inflammation through TNF-α Receptor Signaling

Adult stem cells (SCs) transit between the cell cycle and a poorly defined quiescent state. Single neural SCs (NSCs) with quiescent, primed-for-activation, and activated cell transcriptomes have been obtained from the subependymal zone (SEZ), but the functional regulation of these states under homeostasis is not understood. Here, we develop a multilevel strategy to analyze these NSC states with the aim to uncover signals that regulate their level of quiescence/activation. We show that transitions between states occur in vivo and that activated and primed, but not quiescent, states can be captured and studied in culture. We also show that peripherally induced inflammation promotes a transient activation of primed NSCs (pNSCs) mediated by tumor necrosis factor alpha (TNF-alpha) acting through its receptor, TNF receptor 2 (TNFR2), and a return to quiescence in a TNF receptor 1 (TNFR1)-dependent manner. Our data identify a signaling pathway promoting NSC alertness and add to the emerging concept that SCs can respond to the systemic milieu.

Automated summary

This research focuses on analyzing different states of single neural stem cells (NSCs) obtained from the subependymal zone (SEZ) and identifies that activated and primed states can be captured and studied in culture, while the quiescent state cannot. Additionally, the study shows that peripherally induced inflammation transiently activates primed NSCs via tumor necrosis factor alpha (TNF-alpha) and returns them to quiescence in a TNF receptor 1 (TNFR1)-dependent manner, suggesting a signaling pathway promoting NSC alertness and the ability of stem cells to respond to the systemic environment.