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Autofluorescence is a biomarker of neural stem cell activation state [Subventricular zone]

ABSTRACT: Neural stem cells (NSCs) in the adult brain are primarily quiescent but can activate and enter the cell cycle to produce newborn neurons. NSC quiescence can be regulated by disease, injury, and age, however our understanding of NSC quiescence is limited by technical limitations imposed by the bias of markers used to isolate each population of NSCs and the lack of live-cell labeling strategies. Fluorescence lifetime imaging (FLIM) of autofluorescent metabolic cofactors has previously been used in other cell types to study shifts in cell states driven by metabolic remodeling that change the optical properties of these endogenous fluorophores. Here we asked whether autofluorescence could be used to discriminate NSC activation state. We found that quiescent NSCs (qNSCs) and activated NSCs (aNSCs) each have unique autofluorescence intensity and fluorescence lifetime profiles. Additionally, qNSCs specifically display an enrichment of a specific autofluorescent signal localizing to lysosomes that is highly predictive of cell state. These signals can be used as a graded marker of NSC quiescence to predict cell behavior and track the dynamics of quiescence exit at single cell resolution in vitro and in vivo. Through coupling autofluorescence imaging with single-cell RNA sequencing in vitro and in vivo, we provide a high-resolution resource revealing transcriptional features linked to rapid NSC activation and deep quiescence. Taken together, we describe a single-cell resolution, non-destructive, live-cell, label-free strategy for measuring NSC activation state in vitro and in vivo and use this tool to expand our understanding of adult neurogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE223093 | GEO | 2024/02/09

REPOSITORIES: GEO

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Autofluorescence is a biomarker of neural stem cell activation state [Hippocampus]

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Single-cell RNA-sequencing of adult neural stem cells reveals novel molecular principles of stem cell activation and heterogeneity

Project description:Neural stem cells (NSCs) in the subventricular zone (SVZ) and the subgranular zone of the hippocampus continuously give rise to glial cells and neurons and are the most important source for new neurons in the adult mammalian brain1-4. It has been suggested that the NSCs in the adult brain form a heterogeneous population5,7, akin to other tissue-specific adult stem cells6. However, a molecular basis of the presumed NSC heterogeneity has been lacking. Here, we sequenced the transcriptomes of 131 individual adult NSCs from the mouse SVZ. After filtering, 117 cells were used for further analysis. We found that they consist of two distinct subgroups of about equal size, independent of the mouse’s age. These subgroups were separated by molecular markers of quiescence (quiescent NSCs, qNSCs) and cell-cycle progression (active NSCs, aNSCs). We identified novel cell surface markers belonging to the tetraspanin family of transmembrane proteins for the prospective purification of qNSCs and aNSCs. The individual NSC transcriptomes were ordered along a continuous progression from qNSCs to aNSCs, with the expression of molecular pathways decreasing (G-protein-coupled receptor signaling) or increasing (MAP kinase, PI3 kinase-mTOR, Hippo, and p53 pathways) in a coordinated manner. Within the aNSCs, transcription factors for neural cell lineage specification were expressed in patterns that indicate specific lineage commitment of individual aNSC. Together, these findings imply that the switch from qNSC to aNSC is irreversible in vivo, at least in a large fraction of cells, and is accompanied by lineage commitment already at the stem-cell stage. Thus our work reveals coherent patterns of molecular heterogeneity within adult NSCs that arise from the regulation of cell-cycle activity and differentiation pathways. We also sequenced 13 bulk populations.

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