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Review
. 2015 Aug;63(8):1452-68.
doi: 10.1002/glia.22850. Epub 2015 May 12.

Reactive astrocytes as neural stem or progenitor cells: In vivo lineage, In vitro potential, and Genome-wide expression analysis

Magdalena Götz  1   2   3 , Swetlana Sirko  1   2 , Johannes Beckers  4   5   6 , Martin Irmler  4
Affiliations
Review

Reactive astrocytes as neural stem or progenitor cells: In vivo lineage, In vitro potential, and Genome-wide expression analysis

Magdalena Götz et al. Glia. 2015 Aug.

Abstract

Here, we review the stem cell hallmarks of endogenous neural stem cells (NSCs) during development and in some niches of the adult mammalian brain to then compare these with reactive astrocytes acquiring stem cell hallmarks after traumatic and ischemic brain injury. Notably, even endogenous NSCs including the earliest NSCs, the neuroepithelial cells, generate in most cases only a single type of progeny and self-renew only for a rather short time in vivo. In vitro, however, especially cells cultured under neurosphere conditions reveal a larger potential and long-term self-renewal under the influence of growth factors. This is rather well comparable to reactive astrocytes in the traumatic or ischemic brain some of which acquire neurosphere-forming capacity including multipotency and long-term self-renewal in vitro, while they remain within their astrocyte lineage in vivo. Both reactive astrocytes and endogenous NSCs exhibit stem cell hallmarks largely in vitro, but their lineage differs in vivo. Both populations generate largely a single cell type in vivo, but endogenous NSCs generate neurons and reactive astrocytes remain in the astrocyte lineage. However, at some early postnatal stages or in some brain regions reactive astrocytes can be released from this fate restriction, demonstrating that they can also enact neurogenesis. Thus, reactive astrocytes and NSCs share many characteristic hallmarks, but also exhibit key differences. This conclusion is further substantiated by genome-wide expression analysis comparing NSCs at different stages with astrocytes from the intact and injured brain parenchyma.

Keywords: brain injury; lineage; potential; radial glial cells; self-renewal; transcriptome.

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Figures

Figure 1
Figure 1
Distinction between LINEAGE and POTENTIAL of a single embryonic RGC, adult NCS, and proliferating reactive astrocyte from the adult cerebral cortex. Radial glial cells (RGCs) with their main contacts at the apical side and the basement membrane are widespread in the developing vertebrate CNS and persist into adulthood in the highly specialized stem cell niches and are referred to as adult NSCs. Adult NSCs possess radial glia hallmarks, such as apical contact with the ventricle and a shortened basal process. Both RGCs and adult NSCs are able to generate neurons and glia cells, but at the single‐cell level they are largely uni/bilineage in vivo. In contrast, the injury‐induced proliferation of parenchymal astrocytes, unlike RGCs/NSCs, resulted in the generation of astrocytes only. Even when proliferating reactive astrocytes are astroglial‐restricted, they show a larger potential when exposed to a different environment in vitro, and in similarity to RGCs or NSCs can be instructed to multipotency and long‐term self‐renewal upon exposure to growth factors. VZ, ventricular zone; SEZ, subependymal zone; GM, gray matter of cerebral cortex.
Figure 2
Figure 2
The lineage heterogeneity of radial glial cells from the cerebral cortex of embryonic day 14 mice. Radial glial cells comprise different sets of progenitors, relating to differences in gene expression and neurogenic capacity. Indirectly neurogenic RGCs generate intermediate basal progenitors and had higher levels of hGFAP‐GFP (hGFAP‐GFPhigh), while RGCs that give rise directly to neurons had lower levels of GFP (hGFAP‐GFPlow). These subtypes of RGCs can be separated from the cerebral cortex at E14 on the basis of the level of GFAP‐driven GFP and the different modes of neurogenesis from radial glial cells were revealed by live imaging (for review, see Götz, 2013).
Figure 3
Figure 3
The comparative genome‐wide analysis of different astroglial cell sets from the embryonic and adult mouse forebrain. Genes significantly enriched (more than fivefold) in reactive astrocytes (Reactive AC CTX GM), adult NSCs from the subependymal zone (aNSC SEZ), and RGCs from different stages and regions of the telencephalon (E14 RGC CTX, E18 RGC CTX, and E14 RGC GE) in comparison to protoplasmic astrocytes (AC CTX GM) are plotted as a heat map to illustrate similarity in gene expression between astrocytes sorted from the injured adult mouse cerebral cortex at the peak of their proliferative activity and RGCs/NSCs (the normalized values are plotted on a log2 color scale, with blue representing low expression and red representing high expression) (A). Thirty‐six candidate genes derived from (A) whose expression differs significantly between cells with stem cell or progenitor phenotype and mature astrocytes (B). (C) Bars show the significantly enriched GO terms associated with the candidate genes listed in B. AC, astrocyte; CTX, cortex; E, embryonic day; GE, ganglionic eminence; GM, gray matter; NSC, neural stem cell.
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