Interferon regulates neural stem cell function at all ages by orchestrating mTOR and cell cycle

Abstract

Stem cells show intrinsic interferon signalling, which protects them from viral infections at all ages. In the ageing brain, interferon signalling also reduces the ability of stem cells to activate. Whether these functions are linked and at what time interferons start taking on a role in stem cell functioning is unknown. Additionally, the molecular link between interferons and activation in neural stem cells and how this relates to progenitor production is not well understood.Here we combine single-cell transcriptomics, RiboSeq and mathematical models of interferon to show that this pathway is important for proper stem cell function at all ages in mice. Interferon orchestrates cell cycle and mTOR activity to post-transcriptionally repress Sox2 and induces quiescence. The interferon response then decreases in the subsequent maturation states. Mathematical simulations indicate that this regulation is beneficial for the young and harmful for the old brain. Our study establishes molecular mechanisms of interferon in stem cells and interferons as genuine regulators of stem cell homeostasis and a potential therapeutic target to repair the ageing brain.

Stat1 is an inducible transcriptional repressor of neural stem cells self-renewal program during neuroinflammation

“…There is recent interest in defining the impact of interferons in the SVZ, and recent work has shown an important role of interferons in regulating SVZ NSCs in young and old mice. Type I interferon modulates the activation of SVZ NSCs and induces quiescence ( Kalamakis et al, 2019 ; Carvajal Ibañez et al, 2023 ). At the same time, other groups report major contributions of type I interferon signaling in the aging choroid plexus and ventricular zones ( Baruch et al, 2014 ).…”

“…Furthermore, IFN-γ, through activation of its canonical STAT1 pathway, acts specifically on Nestin + progenitors to decrease progenitor proliferation and the number of cycling cells in a normal SVZ ( Pereira et al, 2015 ). Moreover, a recent paper demonstrated type I interferon induces cell cycle arrest and quiescence of SVZ NSCs ( Carvajal Ibañez et al, 2023 ). Still, the transcriptional targets of Stat1 and the direct role of Stat1 in the regenerative program of NSCs in neuroinflammation as seen in MS due to IFN-γ are still unknown.…”

Identification of astrocyte-driven pseudolineages reveals clinical stratification and therapeutic targets in Glioblastoma

“…Our SVZ NSC reference lineage is comprised of adult WT SVZ NSCs and progeny from three studies 8,13,14 . We incorporated cells from 15 to supplement our SVZ lineage and compare celltype labels.…”

3D printing of interferon γ-preconditioned NSC-derived exosomes/collagen/chitosan biological scaffolds for neurological recovery after TBI

“…Physiological concentrations of IFN-γ notably enhanced neuronal differentiation in vitro [ 33 ]. Moreover, further research indicated that IFN regulates the cell cycle of NSCs by suppressing the expression of SOX2 [ 34 ]. Furthermore, IFN-γ protected NSCs from central nervous system (CNS) infection-related damage through immune-related bystander effects [ 33 ].…”