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Heterogeneity of Reactive Astrocytes


Heterogeneity of Reactive Astrocytes

Mark A Anderson et al. Neurosci Lett.


Astrocytes respond to injury and disease in the central nervous system (CNS) with a process referred to as reactive astrogliosis. Recent progress demonstrates that reactive astrogliosis is not a simple all-or-none phenomenon, but is a finely gradated continuum of changes that range from reversible alterations in gene expression and cell hypertrophy, to scar formation with permanent tissue rearrangement. There is now compelling evidence that reactive astrocytes exhibit a substantial potential for heterogeneity at multiple levels, including gene expression, cell morphology, topography (distance from lesions), CNS regions, local (among neighboring cells), cell signaling and cell function. Structural and functional changes are regulated in reactive astrocytes by many different potential signaling events that occur in a context dependent manner. It is noteworthy that different stimuli of astrocyte reactivity can lead to similar degrees of GFAP upregulation while causing substantially different changes in transcriptome profiles and cell function. Thus, it is not possible to equate simple and uniform measures such as cell hypertrophy and upregulation of GFAP expression with a single, uniform concept of astrocyte reactivity. Instead, it is necessary to recognize the considerable potential for heterogeneity and determine the functional implications of astrocyte reactivity in a context specific manner as regulated by specific signaling events.

Keywords: Autoimmune disease; Glial scar; Heterogeneity; Inflammation; Reactive astrogliosis; Trauma.

Conflict of interest statement

The authors have no financial conflicts or interests


Fig. 1
Fig. 1
Schema depicts multiple levels at which reactive astrocytes can exhibit heterogeneity.
Fig. 2
Fig. 2. Photomicrographs depict heterogeneity of reactive astrocytes that form scar borders around tissue lesions or are distant to focal tissue lesions
Images show mouse spinal cord stained for GFAP (blue) and a reporter protein (red) derived from the MADM system of sparsely labeling astrocytes. (A) In uninjured tissue, astrocyte processes labeled with GFAP or reporter protein respect individual cellular domains. (B) In tissue somewhat removed from an SCI lesion, the processes of hypertrophic astrocytes exhibit some, but minimal overlap. (C) In the astrocyte scar border that immediately abuts and surrounds the SCI lesion core (LC), the cell processes of elongated astrocytes overlap, make contacts and intertwine extensively. Adapted from [54].
Fig. 3
Fig. 3. Photomicrographs depict heterogeneity of reactive astrocytes in response to different timuli (A, B), as well as local heterogeneity of reactive astrocytes in response to the same stimulus (B)
Images show mouse cerebral cortex stained for GFAP (green) or the chemokine CCL7 (red) after injection of either PBS (A) or the inflammatory mediators, LPS+IFNγ+TGFβ in PBS, (B). Green arrowheads indicate reactive astrocytes that express only GFAP, red arrowheads indicate microglia or macrophages that express CCL7, and yellow arrowheads indicate reactive astrocytes that express both GFAP and CCL7. After injection of PBS, reactive astrocytes stain only for GFAP (green) and no reactive astrocytes have upregulated expression of CCL7 (A). After injection of LPS+IFNγ+TGFβ in PBS, many reactive astrocytes have upregulated both GFAP and CCL7 (yellow arrows) and these are intermingled with some reactive astrocytes that have not upregulated CCL7 and are positive only for GFAP (green arrowheads) (B). Adapted from [21].

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