Sankowski R, Böttcher C, Masuda T, Geirsdottir L, Sagar, Sindram E, Seredenina T, Muhs A, Scheiwe C, Shah MJ, Heiland DH, Schnell O, Grün D, Priller J, Prinz M. Mapping microglia states in the human brain through the integration of high-dimensional techniques. Nat Neurosci. 2019 Nov 18; PubMed. Correction.
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Washington University School of Medicine
Several studies have unveiled an important phenotypic heterogeneity of mouse microglia. Yet our understanding of the human microglia is limited, especially because of the technical difficulties to obtaining fresh brain tissues from human donors. Nonetheless, a few recent studies have indicated that, like the mouse, the human brain harbors a variety of microglial phenotypes that possibly reflect different topological locations and/or different functions. In this regard, this recent work by Sankowski et al. provides a detailed characterization of human microglia using a combination of single-cell RNA-Seq, CyTOF, and immunohistochemistry. Overall, this study generates a large amount of transcriptomic and proteomic information, defining microglial phenotype in both gray and white matter from individuals with either epilepsy or cancer, but no obvious brain abnormalities, including older individuals. Additionally, this work presents the first transcriptomic description of microglia, at single-cell resolution, within the human glioblastoma.
Sankowski and colleagues perform scRNA-Seq on microglia from 15 subjects, ranging from 14 to 74 years old. Sorting CD45+ cells, the authors could successfully identify a major microglia population, but also a minor fraction of monocytes, T cells, and oligodendrocytes. Microglia from biopsied brain tissue formed eight distinct clusters, highlighting the presence of multiple phenotypic subsets under homeostasis. The majority of microglia were enriched for homeostatic signature genes (Cx3cr1, Tmem119, Csf1r, P2ry12, Selplg). Another main population expressed high levels of antigen-presentation genes (HLA-DR and CD74), indicating an immune-activated state. However, other minor subsets were enriched for inflammatory genes (Spp1, ApoE, LPL, Ccl2, Il1b and IFN-associated genes). Such a phenotypic diversity may reflect a different distribution within the brain parenchyma. Indeed, authors showed that white-matter microglia expressed high levels of HLA-DR, ApoE, CD68, and F4/80, whereas gray matter microglia exhibited a relatively low expression of these genes.
The authors also show that the microglia phenotype changes during aging. Indeed, microglia from young individuals were mostly characterized by a homeostatic signature. By contrast, microglia from senile subjects exhibited an increased expression of inflammatory genes (like Spp1), especially in the white matter. These data show that microglial phenotype in the human brain is instructed by the local environment (i.e., gray vs. white matter) and becomes more proinflammatory during aging.
Lastly, Sankowski and colleagues show that glioblastoma-associated microglia are remarkably heterogeneous. For example, one cluster matched the microglial phenotype of the healthy subjects. Conversely, a distinct population exhibited a significant upregulation of antigen-presentation (HLA-DR), inflammatory (Spp1, ApoE, Trem2), and interferon-signature genes, resembling more closely the phenotype of age-associated microglia. Additional studies are needed to determine whether this population is capable of presenting tumor antigens to T cells, thus eliciting an anti-tumor response. Additionally, another population was enriched for hypoxia-induced genes such as Hif1a and VEGFA. This population may encompass those microglial cells located in the most inner part of the tumor mass, which is notoriously highly hypoxic. Alternatively, this subset may define a pro-angiogenic phenotype, which may then represent a suitable target for therapy.
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