High-resolution mouse subventricular zone stem-cell niche transcriptome reveals features of lineage, anatomy, and aging

Significance Adult neural stem cells (NSC) are closely related to multiple neurological disorders and brain tumors. Comprehensive investigation of their composition, lineage, and aging will provide insights that may lead to enhanced patient treatment. This study applies a transgene to label and manipulate neural stem/progenitor cells and monitor their evolution during aging. Together with high-throughput single-cell RNA sequencing, we are able to analyze the subventricular zone cells from infancy to advanced age with unprecedented granularity. Diverse cell states are identified in the stem-cell niche, and an aging-related NSC deficiency in transition from quiescence to proliferation is identified. The related biological features provide rich resources to inspect adult NSC maintenance and neurogenesis. Adult neural stem cells (NSC) serve as a reservoir for brain plasticity and origin for certain gliomas. Lineage tracing and genomic approaches have portrayed complex underlying heterogeneity within the major anatomical location for NSC, the subventricular zone (SVZ). To gain a comprehensive profile of NSC heterogeneity, we utilized a well-validated stem/progenitor-specific reporter transgene in concert with single-cell RNA sequencing to achieve unbiased analysis of SVZ cells from infancy to advanced age. The magnitude and high specificity of the resulting transcriptional datasets allow precise identification of the varied cell types embedded in the SVZ including specialized parenchymal cells (neurons, glia, microglia) and noncentral nervous system cells (endothelial, immune). Initial mining of the data delineates four quiescent NSC and three progenitor-cell subpopulations formed in a linear progression. Further evidence indicates that distinct stem and progenitor populations reside in different regions of the SVZ. As stem/progenitor populations progress from neonatal to advanced age, they acquire a deficiency in transition from quiescence to proliferation. Further data mining identifies stage-specific biological processes, transcription factor networks, and cell-surface markers for investigation of cellular identities, lineage relationships, and key regulatory pathways in adult NSC maintenance and neurogenesis.

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