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Review
. 2018 Jan;21(1):9-15.
doi: 10.1038/s41593-017-0033-9. Epub 2017 Dec 21.

The Diversity and Disparity of the Glial Scar

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Free PMC article
Review

The Diversity and Disparity of the Glial Scar

Katrina L Adams et al. Nat Neurosci. .
Free PMC article

Abstract

Injury or disease to the CNS results in multifaceted cellular and molecular responses. One such response, the glial scar, is a structural formation of reactive glia around an area of severe tissue damage. While traditionally viewed as a barrier to axon regeneration, beneficial functions of the glial scar have also been recently identified. In this Perspective, we discuss the divergent roles of the glial scar during CNS regeneration and explore the possibility that these disparities are due to functional heterogeneity within the cells of the glial scar-specifically, astrocytes, NG2 glia and microglia.

Conflict of interest statement

Competing interests

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1. Cellular interactions in the glial scar
a, Diagram of the glial scar after spinal cord injury. The glial scar is made up of reactive astrocytes (orange), NG2 glia (teal) and microglia (purple) that form a tight barrier around the lesion core, or area of severe tissue damage. The lesion core contains blood-borne macrophages (gray) and stromal cells (yellow). Injured axons (gray lines) fail to grow through the glial scar. b, The cellular interactions and developmental potential of heterogeneous glial cells within the glial scar (boxed region in a). Black arrows indicate the in vivo and in vitro lineage potential of each glial cell type, with black dashed arrows representing less common cell fates (that is, NG2 glial differentiation into Schwann cells or reactive astrocytes). Green lines depict cellular interactions among glial cells in the scar. Specifically, M1 microglia promote an A1 reactive astrocyte phenotype, while M2 microglia have been shown to promote differentiation of NG2 glia to oligodendrocytes. A1 reactive astrocytes secrete a toxin that kills oligodendrocytes. Blue lines depict the effect of each cell type on axonal growth (blue arrow indicates promotion of axon growth while blunt end indicates inhibition). The A1 and A2 astrocyte subtypes are based on Liddelow et al. while the M1 and M2 microglial subtypes are based on Miron et al.. NSCs, neural stem cells.
Fig. 2
Fig. 2. Tools for assessing functional cellular diversity in glia
Elucidating cellular diversity requires robust purification protocols that effectively isolate astrocytes, NG2 glia or microglia from surrounding CNS tissue. Once cells are purified, they can be characterized using a range of different molecular tools, including new techniques such as single-cell RNA sequencing and translating ribosome affinity purification (TRAP) sequencing. These techniques result in molecular profiles that can be used to identify new molecular markers for glial subtypes, potential physiological differences among cellular subtypes and potential therapeutic targets for promoting functional repair following CNS damage. Assessing cellular physiology is critical for understanding functional heterogeneity of astrocytes, NG2 glia and microglia. While in vitro assays (for example, cellular proliferation and synapse modulation) and in vivo imaging techniques have been used to characterize all three glial populations, there is a lack of sophisticated tools for analyzing microglial physiology. Refs. for purification protocols: Zhang et al., Lin et al., Bennett et al.. Refs. for molecular tools: Doyle et al., Kim et al.. Refs. for physiology: Nimerjahn et al., Perea et al., Larson et al., Gee et al..

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