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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE66460 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:Throughout postnatal life in mammals, neural stem cells (NSCs) are located in the subventricular zone (SVZ) of the lateral ventricles. The greatest diversity of neuronal and glial lineages they generate occurs during early postnatal life in a region-specific manner. In order to evaluate potential heterogeneity in the NSC pool, we microdissected the dorsal and lateral SVZ at different postnatal ages and isolated NSCs and their immediate progeny based on their expression of Hes5-EGFP/Prominin1 and Ascl1-EGFP, respectively. Whole genome comparative transcriptome analysis revealed transcriptional regulators as major hallmarks that sustain postnatal SVZ regionalization. Manipulation of single genes encoding for locally enriched transcription factors influenced NSC specification indicating that the fate of regionalized postnatal SVZ NSCs can be readily modified . These findings reveal functional heterogeneity of NSCs in the postnatal SVZ and provide targets to recruit region-specific lineages in regenerative contexts. Microarrays of neural stem cells, early progenitors and the tissue from subregions of the subventricular zone were compiled to screen for the full extent of heterogeneity in this region during postnatal life. Spatially distinct regions of the developing forebrain subventricular zone (SVZ) aged at P4, P8 and P11 were microdissected in RNAse free/sterile conditions. Mice expressing Ascl1-EGFP in the SVZ were used to aid accurate microdissection of the dorsal and lateral wall of each of the studied time points as per our previous publications characterizing this method. As well as at the whole microdomain level, additionally, NSCs (Hes5-EGFP+/Prom1+) and early progenitors (Ascl1-EGFP+) from each microdomain were further isolated by FAC sorting methods. This was to provide a comprehensive gene expression analysis at the tissue level and at the cellular level. Generally, 1 litter was used to yield 1 'n' number of replicates. A total of 23 affymetrix analysis were performed.

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

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