Identification of diverse astrocyte populations and their malignant analogs

Abstract

Astrocytes are the most abundant cell type in the brain, where they perform a wide array of functions, yet the nature of their cellular heterogeneity and how it oversees these diverse roles remains shrouded in mystery. Using an intersectional fluorescence-activated cell sorting–based strategy, we identified five distinct astrocyte subpopulations present across three brain regions that show extensive molecular diversity. Application of this molecular insight toward function revealed that these populations differentially support synaptogenesis between neurons. We identified correlative populations in mouse and human glioma and found that the emergence of specific subpopulations during tumor progression corresponded with the onset of seizures and tumor invasion. In sum, we have identified subpopulations of astrocytes in the adult brain and their correlates in glioma that are endowed with diverse cellular, molecular and functional properties. These populations selectively contribute to synaptogenesis and tumor pathophysiology, providing a blueprint for understanding diverse astrocyte contributions to neurological disease.

Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis

“…To test this hypothesis, we used two different mouse models of glioma that harness in utero electroporation (IUE) of the embryonic cortex to facilitate gene manipulation. One model utilizes CRISPR/Cas9 (herein CRISPR/IUE) 31 gene editing of NF1 , PTEN , and p53, tumor suppressors that are commonly mutated in human glioma 32–34 , while the other utilizes PiggyBac (PB) targeting of glial lineages with oncogenic Ras to produce malignant glioma (herein PB-Ras/IUE) (Supplemental Figure S7; 28,35 ). Mutations in Ras are rare in glioma, however EGFR , PDGFR , and NF1 are frequently mutated and all of these pathways signal through Ras.…”

“…Alternatively, given that Sox9 and NFIA both antagonize Olig2 function, it may be that they function in glioma cell lineages downstream of stem cells to promote differentiation into pathological glia, which importantly, comprise the vast majority of the bulk tumor. Indeed our recent studies have identified several astrocyte-like subpopulations of cells within mouse and human glioma 31 , and it may be that the NFIA, Sox9, Brn2 node functions to promote the differentiation of these populations during tumorigenesis. Future studies will be aimed at understanding the role of Sox9, NFIA, and Brn2 in glioma stem cells, how these new transcriptional nodes influence the production of diverse glioma cell populations, and the nature of their relationship with the glioma stem cell transcriptional node.…”

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…The functional and molecular diversity of astrocytes in normal, and especially in diseased brains, remains challenging (Haim & Rowitch, 2017). The extensive array of astrocyte functions supports the existence of different astroglial populations, and, recently, five distinct subpopulations based on molecular profiles have been identified in the adult mouse brain (John Lin et al, 2017). Noteworthy, one of the populations (type C) is highly enriched for genes associated with synaptic activity, and two subpopulations (types B and C) for genes associated with phagocytic capacity.…”

“…The discovery that astrocytes express receptors and downstream signaling molecules involved in phagocytic pathways (Cahoy et al, 2008) supports new physiological roles for these cells, including the phagocytosis of synapses, both during development and in the adult brain (Chung et al, 2013). Further supporting a phagocytic profile, a recent study has described different astrocyte subpopulations by their specific gene signatures in adult mouse brain, and, interestingly, some subsets are enriched in genes linked to phagocytosis (John Lin et al, 2017). However, reactive astrocytes might display disease‐specific dysfunctional phenotypes and thus contribute to circuit failure and disease progression.…”

“…Astrocyte reactivity is specifically identified in the vicinity of amyloid plaques and can be monitored by the increased expression of the intermediate filament protein, GFAP, and, morphologically, by the hypertrophy of their main processes (Osborn et al, 2016; Verkhratsky, Zorec, Rodriguez, & Parpura, 2016). Though emerging data support the molecular and functional diversity of astrocytes in adult brain (Haim & Rowitch, 2017; John Lin et al, 2017), little is known about disease‐activated astrocyte diversity. The activation of astrocytes has been often viewed as a neuroinflammatory toxic response in AD; however, this concept is currently changing to the notion of loss‐of‐function (Masgrau, Guaza, Ransohoff, & Galea, 2017) or protection.…”