Dissecting the Population Structure of Human Microglia and its Relation to Neuropathologic Traits and Diseases

Philip L De Jager MD PhD, Weil-Granat Professor of Neurology, Columbia University Medical Center, Chief of the Division of Neuroimmunology

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of their phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived brain samples, we identified 9 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other neurological and neurodevelopmental diseases and disorders. Several human microglia sub-populations show enrichment for genes found in disease-associated mouse microglial states. Overall, human microglia exist in different functional states with varying levels of association with different brain pathologies.