Cross-Analysis of Single-Cell Transcriptomic Datasets Reveals Conserved Neurogenic Gene Signatures and New Insights Into Neural Stem Cell Aging

Hippocampal adult neural stem cells (NSCs) contribute to neurogenesis and astrogliogenesis throughout life. They play multifaceted roles in hippocampal function, including memory processing, stress regulation, and cognitive flexibility. Located in unique neurogenic niches like the subgranular zone of the hippocampal dentate gyrus, NSCs exhibit notable heterogeneity and can be classified into quiescent, activated, and intermediate transitioning states. This diversity, while instrumental to their adaptability and function, presents challenges in molecular classification and functional interrogation. Here, we discuss current limitations and compare NSC transcriptional profiles from publicly available single-cell RNA sequencing datasets. We address discrepancies in NSC classification between studies, identify conserved gene expression profiles, and propose new markers that could serve as standardized references. Furthermore, we explore how pseudotime inference analyses provide insights into the temporal dynamics of NSCs and their progression toward neural progenitors, further aiming to optimize their classification. We also examine cellular changes in NSCs during aging and explore the potential of these cells to undergo senescence. Our work helps to resolve inconsistencies in current cell-type annotations in literature and proposes a framework to study and classify the different states of NSCs, thereby offering a better understanding of their dynamic roles in neurogenesis, aging, and cellular senescence.