Astrocyte maturation creates a stage-specific niche that instructs hippocampal neurogenesis

Astrocytes are a major part of the hippocampal stem cell niche and have been shown to control several steps of neurogenesis, from neural stem and precursor cell (NSPC) proliferation to the differentiation and maturation of newborn neurons. With the aim to identify new factors by which astrocytes promote neurogenesis, we isolated hippocampal astrocytes across key postnatal stages (p3, p10, and p14) and collected astrocyte conditioned medium (ACM) while keeping them for 1 week in culture. Depending on the developmental stage of the astrocytes, we uncovered a shift in the astrocyte secretome. Specifically, ACM from p3 progenitor-like astrocytes promoted a gliogenic program when applied to adult hippocampal NSPCs, while ACM derived from p10 and p14 astrocytes exhibited potent neurogenic properties. To define the molecular basis underlying the acquisition of these neurogenic properties, we performed transcriptomic profiling of astrocytes directly isolated at p3, p10 and p14 as well as astrocytes isolated at these stages that were kept in culture for 7 days. These data sets were integrated with metabolomic analysis of astrocyte-conditioned media from p3 and p14 astrocytes revealing distinct stage-specific programs enriched for secretory and metabolic pathways. Notably, we identified a combination of metabolites that accumulates as astrocytes mature and act as potent drivers of neuronal differentiation. Our findings demonstrate that astrocyte maturation establishes a metabolically and transcriptionally defined, stage-specific niche that instructs NSPC fate and drives neurogenesis.