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

Abstract

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 data sets allow precise identification of the varied cell types embedded in the SVZ including specialized parenchymal cells (neurons, glia, microglia), and non-central 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.Significance StatementAdult neural stem cells (NSC) are closely related to multiple neurological disorders and brain tumors. Comprehensive investigation of their composition, lineage, and aging will provide new insights that may lead to enhanced patient treatment. This study applies a novel 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 (SVZ) cells from infancy to advanced age with unprecedented granularity. Diverse new 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.

Single-cell analysis of the ventricular-subventricular zone reveals signatures of dorsal and ventral adult neurogenesis

“…A fraction of both populations expressed Gfap: 51.85% of B cells (clusters 5,13,14 & 22) and 24.37% of parenchymal astrocytes (clusters 21, 26 & 29). This is consistent with previous reports (Chai et al, 2017;Ponti et al, 2013;Xie et al, 2020b). Note that across all cells captured in our scRNAseq analysis, only B cells, parenchymal astrocytes or ependymal cells expressed high levels of Gfap.…”

“…Previous single-cell sequencing experiments in the V-SVZ have described the many broad classes of cells that reside in the niche. For example, transcriptional analyses after cell sorting have identified stages in the B-C-A cell lineage (Borrett et al, 2020;Codega et al, 2014;Dulken et al, 2017;Xie et al, 2020a), as well as populations of NSPCs that appear to activate after injury (Llorens-Bobadilla et al, 2015). Profiling of the entire niche has highlighted differences between quiescent and activated B cells (Mizrak et al, 2020;Zywitza et al, 2018).…”

A Shared Transcriptional Identity for Forebrain and Dentate Gyrus Neural Stem Cells from Embryogenesis to Adulthood

“…What then is the dormant forebrain NSC state? For adult V-SVZ and SGZ NSCs, this dormancy state predominantly involves a downregulation of basic cellular processes such as those required for DNA replication and transcription, RNA processing and translation, ribosome biogenesis, and protein synthesis and folding, in good agreement with what has been described in other studies (Llorens-Bobadilla et al, 2015, Shin et al, 2015, Dulken et al, 2017, Berg et al, 2019, Xie et al, 2020. However, the dormant NSC state involves more than just this shut-down.…”

Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging

“…Increased heterogeneity in gene expression has been found in various stem cells and the niche cells (Hernando-Herraez et al, 2019;Mahmoudi et al, 2019;Salzer et al, 2018;Xie et al, 2020). To delineate the complexity of aging at the stem cell, tissue and organismal level, it is critical to examine changes in the regulatory molecules and pathways simultaneously across cell types and tissues in aging animals.…”