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. 2006 Nov 14;103(46):17513-8.
doi: 10.1073/pnas.0602841103. Epub 2006 Nov 7.

Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury

Ulrika Wilhelmsson  1 , Eric A Bushong, Diana L Price, Benjamin L Smarr, Van Phung, Masako Terada, Mark H Ellisman, Milos Pekny
Affiliations

Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury

Ulrika Wilhelmsson et al. Proc Natl Acad Sci U S A. .

Abstract

Reactive astrocytes in neurotrauma, stroke, or neurodegeneration are thought to undergo cellular hypertrophy, based on their morphological appearance revealed by immunohistochemical detection of glial fibrillary acidic protein, vimentin, or nestin, all of them forming intermediate filaments, a part of the cytoskeleton. Here, we used a recently established dye-filling method to reveal the full three-dimensional shape of astrocytes assessing the morphology of reactive astrocytes in two neurotrauma models. Both in the denervated hippocampal region and the lesioned cerebral cortex, reactive astrocytes increased the thickness of their main cellular processes but did not extend to occupy a greater volume of tissue than nonreactive astrocytes. Despite this hypertrophy of glial fibrillary acidic protein-containing cellular processes, interdigitation between adjacent hippocampal astrocytes remained minimal. This work helps to redefine the century-old concept of hypertrophy of reactive astrocytes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Entorhinal cortex lesion triggers reactive gliosis in the hippocampus. Unilateral entorhinal cortex lesion triggers astrocyte activation in the outer and middle molecular layer of the ipsilateral dentate gyrus of the hippocampus (Right, in gray). Antibodies against GFAP visualize bundles of intermediate filaments predominantly found in the soma and the main cellular processes of astrocytes. Four days after unilateral entorhinal cortex lesioning, astrocytes in the molecular layer of the dentate gyrus on the injured side were reactive and all showed greater GFAP immunoreactivity (Center) than the nonreactive astrocytes on the contralateral side (Left). The square in Right denotes the area corresponding to the images in Left and Center. EC, entorhinal cortex. (Scale bar, 25 μm.)
Fig. 2.
Fig. 2.
Morphological assessment of reactive and nonreactive astrocytes in the hippocampus. (A) Maximum projections of dye-filled reactive and nonreactive astrocytes in the molecular layer of the dentate gyrus 4 days after entorhinal cortex lesioning. Dye-filling revealed fine spongiform processes in reactive astrocytes comparable with those of nonreactive astrocytes but a greater number of main processes extending from the cell soma of reactive astrocytes. (Scale bar, 25 μm.) (B and C) Quantification of main cellular processes leaving the soma (B) and processes visible 25 μm from the cell soma (C). Thick processes were more numerous in reactive astrocytes than in nonreactive astrocytes. Three-dimensional reconstruction (E) shows that reactive and nonreactive astrocytes access similar volumes of tissue (D; unit y axis 103 μm3). Error bars represent SEM.
Fig. 3.
Fig. 3.
Electrically induced lesion of the cerebral cortex triggers astrocyte activation in the surrounding tissue. Four days after injury, reactive astrocytes in the cerebral cortex around the lesion show highly increased GFAP immunoreactivity (A and B). (C) Schematic presentation of the injury with the rectangle corresponding to the area shown in A. An asterisk indicates the necrotic area; the dotted line indicates the injury border. CC, corpus callosum. (Scale bar, 100 μm.)
Fig. 4.
Fig. 4.
Morphological assessment of reactive and nonreactive cortical astrocytes. (A) Maximum projections of dye-filled reactive and nonreactive astrocytes in layer I of cerebral cortex 4 days after cortical lesioning. Dye-filling reveals fine spongiform processes in reactive astrocytes comparable to those of nonreactive astrocytes but a greater number of main processes extending from the cell soma of reactive astrocytes. (Scale bar, 25 μm.) (B and C) Quantification of main cellular processes leaving the soma (B) and processes visible 15 μm from the cell soma (C). Thick processes were more numerous in reactive astrocytes than in nonreactive astrocytes. Three-dimensional reconstruction shows that reactive and nonreactive astrocytes access similar volumes of tissue (D; unit y axis 103 μm3). Error bars represent SEM.
Fig. 5.
Fig. 5.
Overlap between astrocyte territories assessed by dye-filling of neighboring cells (Lucifer yellow and Alexa Fluor 568). Maximum projections of astrocytes in the molecular layer of the dentate gyrus on the lesioned and contralateral sides show adjacent astrocyte territories (domains) on three optical sections 4 μm apart. Insets show territories with overlapping areas in yellow. The extent of interdigitation between neighboring astrocytes, both reactive and nonreactive, was limited and most prominent around blood vessels (arrowheads). (Scale bar 25 μm.)
Fig. 6.
Fig. 6.
The domains of nonreactive and reactive astrocytes—a concept. (A) Interdigitation of fine cellular processes in a 3D reconstruction of astrocytes in the dentate gyrus. The yellow zone shows the border area where cellular processes of two adjacent astrocytes interdigitate. (B) Reactive astrocytes stay within their domains, but their main cellular processes get thicker, making them visible over a greater distance (illustrated here by the circles).
See this image and copyright information in PMC

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