Heterogeneity of human microglia at the single cell level: different clusters relate to different diseases and pathologies Marta Olah, PhD1,2,3,4, Vilas Menon, PhD1,2,3,4, Naomi Habib, PhD4, Mariko Taga, PhD1,2,3,4, Christina Yung, BSc1,2,3,4, Rani Sarkis, MD5, Wassim Elyaman, PhD1,2,3,4, Julie A. Schneider, MD6, David A. Bennett, MD6, Elizabeth M. Bradshaw, PhD1,2,3,4 and Philip L. De Jager, MD, PhD1,2,3,4 1Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, New York, USA; 2Taub Institute for Research on Alzheimer's disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA; 3Department of Neurology, Columbia University Medical Center, New York, New York, USA; 4Broad Institute, Cambridge, Massachusetts, USA; 5Brigham and Women's Hospital, Boston, Massachusetts, USA; 6Rush University Medical Center, Chicago, Illinois, USA
Recently it has been suggested that the potential microglia phenotypic states form a multidimensional space, rather than a linear spectrum encompassing a couple of phenotypes, as historically held. To explore microglia phenotype diversity in an unbiased way, we performed high-throughput single cell RNA sequencing of human microglia. By profiling 16,000 CD45+ cells isolated from the cerebral cortices of 6 aged and 8 middle-aged individuals, we have identified several unique subpopulations of microglia. While some smaller subpopulations were demarcated based on mutually exclusive marker combinations, the bulk of the microglia cells belonged to 5 large clusters that fell along gene expression gradients. We have confirmed the existence of these subpopulations in situ. We also investigated the functional significance of these microglia subpopulations by exploring their relationship to transcriptomic signatures of neurodegenerative diseases and aging, which revealed divergent association of the microglial clusters with different diseases and pathologies.