A single-cell transcriptome atlas of glial diversity in the human hippocampus across the postnatal lifespan

The molecular diversity of glia in the human hippocampus and their temporal dynamics over the lifespan remain largely unknown. Here, we performed single-nucleus RNA sequencing to generate a transcriptome atlas of the human hippocampus across the postnatal lifespan. Detailed analyses of astrocytes, oligodendro-cyte lineages, and microglia identified subpopulations with distinct molecular signatures and revealed their association with specific physiological functions, age-dependent changes in abundance, and disease rele-vance. We further characterized spatiotemporal heterogeneity of GFAP-enriched astrocyte subpopulations in the hippocampal formation using immunohistology. Leveraging glial subpopulation classifications as a reference map, we revealed the diversity of glia differentiated from human pluripotent stem cells and identi-fied dysregulated genes and pathological processes in specific glial subpopulations in Alzheimer's disease (AD). Together, our study significantly extends our understanding of human glial diversity, population dy-namics across the postnatal lifespan, and dysregulation in AD and provides a reference atlas for stem -cell-based glial differentiation.

Automated summary

This study used single-nucleus RNA sequencing to analyze the transcriptome atlas of glia in the human hippocampus. The results revealed distinct molecular signatures of glial subpopulations and their associations with physiological functions, age-dependent changes, and relevance to diseases such as Alzheimer's disease. Furthermore, the study characterized the spatiotemporal heterogeneity of certain astrocyte subpopulations and identified dysregulated genes and pathological processes in specific glial subpopulations in Alzheimer's disease. The findings significantly contribute to our understanding of human glial diversity and the dysregulation in Alzheimer's disease, as well as provide a reference atlas for stem cell-based glial differentiation.