Editors' ChoiceCancer

Astrocytes light up glial heterogeneity

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Science Translational Medicine  01 Mar 2017:
Vol. 9, Issue 379, eaam9858
DOI: 10.1126/scitranslmed.aam9858

Abstract

Functionally diverse subpopulations of astrocytes have correlates in the neoplastic adult brain.

The infinitely complex interactions between neurons, astrocytes, and oligodendrocytes in the mammalian brain highlight the balance that heterogeneous cell populations must establish and maintain to prevent disease. This interplay is further complicated when any one cell population exhibits additional diversity, as has been well studied for neurons but to a much lesser extent for their glial counterparts. In a recent study, Lin et al. report a previously unappreciated amount of heterogeneity for astrocytes in the adult brain with direct functional implications in the normal and neoplastic states.

The authors began their search for distinct astrocyte subpopulations using a pan-astrocyte GFP-reporter mouse along with microdissection of five brain regions. They applied a fluorescence activated cell sorting (FACS)–based approach to examine the expression profile of 81 cell surface antigens and narrowed down the presence or absence of CD51, CD63, and/or CD71 as a signature for five distinct astrocyte subpopulations (termed A, B, C, D, and E). Each subtype was present in varying amounts within each brain region and was confirmed to have a distinct gene expression profile. There was a predominance of populations A, C, and E in early cortical development versus B and D in late development. Furthermore, there was clear functional delineation between A and C in development, with C cells being more proliferative, whereas A cells were more migratory. Functional specificity was also validated in the adult brain, with C cells preferentially supporting synapse formation between neurons.

A key remaining question was what role, if any, these subpopulations of astrocytes play in a disease state. Cellular heterogeneity within brain tumors is well appreciated and has direct clinical implications for disease progression and treatment resistance. A subpopulation of tumor cells, called cancer stem–like cells, preferentially harbors the most malignant properties and is at the apex of therapeutic resistance and tumor recurrence. The authors add a layer of complexity to this model by demonstrating that astrocyte subpopulations similar to those in normal brain exist within patient tumors and in mouse models of glioma and that specific populations contribute to two key features of tumor progression: seizures and invasion.

The identification of such expansive heterogeneity amongst astrocytes generates numerous questions regarding the implications for normal brain development and adult homeostasis, as well as disease states. Understanding what drives each subtype and to what extent there is subtype plasticity could offer new nodes of therapeutic intervention.

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