Single-nucleus transcriptomic sequencing and cross integration comparison of multiple species revealed new cell composition and specific gene marker in hippocampal aging of tree shrew
The brain of the tree shrew (Tupaia belangeri chinensis, TS) has drawn considerable attention due to its high similarities to that of humans. The hippocampal formation is one of the main brain regions affected in aging and neurological diseases. However, the cellular compositions of the TS hippocampus involving in aging development remain elusive. Here we established the first single-nucleus transcriptomic profiles of TS hippocampus and identified 16 cell subpopulations. The cross-species comparison of multi-species hippocampus revealed the cell landscape and associated specific gene expression patterns at the single-cell resolution. We validated ROBO2 and FGF14 as a TS/primate-specific NB[1] marker and confirmed TS-specific neural stem cells (NSCs) with SOX5/SOX6 high expression. Then, we identified TS cell types and molecular pathways closely associated with human neurological disorders, bridging the gap between gene mutations and pathogenesis. Importantly, we established the first single-nucleus transcriptomic atlas of TS hippocampal aging, in which the dynamics of the neurogenic lineage and the diversity of oligodendrocyte and microglia was revealed and delineated. Specifically, the regulatory continuum from adult NSCs to immature and mature granule cells was addressed in the neurogenic lineage. Meanwhile, in-depth dissection of gene-expression dynamics revealed impaired neurogenesis along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and endothelial cells may contribute to a hostile microenvironment for neurogenesis. Together, to our knowledge, this is the first time to report a single-cell atlas of TS in hippocampus aging which therefore provides extensive resources in both cell compositions and specific gene map for future research regarding neural science, evolutionary developmental biology, and regenerative medicine, combined with a comprehensive analysis across species. Overall design: Single-nucleus RNA-sequencing of hippocampus from infancy, adult, and aging tree shrew (Tupaia belangeri chinensis).