Review Article | Published:

The stem cell potential of glia: lessons from reactive gliosis

Nature Reviews Neuroscience volume 12, pages 88104 (2011) | Download Citation

Abstract

Astrocyte-like cells, which act as stem cells in the adult brain, reside in a few restricted stem cell niches. However, following brain injury, glia outside these niches acquire or reactivate stem cell potential as part of reactive gliosis. Recent studies have begun to uncover the molecular pathways involved in this process. A comparison of molecular pathways activated after injury with those involved in the normal neural stem cell niches highlights strategies that could overcome the inhibition of neurogenesis outside the stem cell niche and instruct parenchymal glia towards a neurogenic fate. This new view on reactive glia therefore suggests a widespread endogenous source of cells with stem cell potential, which might potentially be harnessed for local repair strategies.

Key points

  • Glial cells are the main cellular elements mediating the reaction to brain and CNS injury.

  • Recently, the consequences of the multifaceted reaction of astroglia towards injury has been examined by attenuating this response or ablating proliferating reactive astrocytes in mouse mutants. This has revealed several beneficial effects at early stages as well as less beneficial effects at later stages after injury.

  • Reactive astrocytes reactivate many molecular hallmarks of radial glial cells. Even more strikingly, genetic fate mapping demonstrated the dedifferentiation of mature astroglial cells that resume proliferation, with a subpopulation even acquiring neurosphere-forming capacity — that is, the in vitro stem cell hallmarks of self-renewal and multipotency. Thus, some of the signals activated after brain injury may be shared with the neural stem cell niche.

  • In vivo, however, these and other glial cells reacting to injury remain within the glial lineage and fail to generate neurons — similar to most of the transplanted cells derived from adult neuroblasts or neural stem cell preparations. Thus, there are potent inhibitors of neurogenesis in the injured brain environment.

  • To dissect the beneficial effects from adverse effects of the glial response to injury, we first consider signals shared between the adult neural stem cell niches and the reaction to injury. These are mostly growth factors, such as epidermal growth factor, fibroblast growth factor and vascular endothelial growth factor, acting on the mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathway as a common mediator, as well as sonic hedgehog (SHH), WNT and purinergic signalling pathways shared between the stem cell niches and the injured brain parenchyma. These would therefore be prime candidates to enhance the dedifferentiation response of reactive astrocytes.

  • Signal transducer and activator of transcription (STAT) signalling is particularly elevated after brain injury, mediating many crucial aspects of reactive astrocytosis, but also interfering with neurogenesis, especially in combination with the bone morphogenetic protein (BMP) signalling pathway.

  • Endogenous BMP levels in the neural stem cell niche of the subependymal zone conversely promote neurogenesis, thereby highlighting the context-dependence of these signals.

  • Thus, much more needs to be learnt about the complex interplay of signals within the neural stem cell niches and the brain parenchyma reacting to injury. In particular, cell type-specific transcriptome information in different injury conditions also needs to be acquired and compared to expression profiles of neural stem cells in their neurogenic environment.

  • The utility of learning from the neurogenic niches in the adult brain is demonstrated by two key examples: first, by the ability of neuroblasts from these niches to react to injury, migrate there and overcome the inhibitory signals emanating from the injury site; and second, by the ability of single neurogenic factors to instruct neurogenesis from glial cells in the injury site in vivo or in vitro.

  • A major challenge is now to extend these exciting findings to the human condition with the aim of better understanding reactive gliosis in patients' brains and potentially using this knowledge and these cells for instructing endogenous repair.

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Acknowledgements

We apologize to investigators whose work could not be cited owing to space limitations. We are grateful to members of the Götz laboratory for fruitful discussions and are particularly indebted to L. Dimou, A. Grande, C. Heinrich, J. Ninkovic and S. Sirko for their helpful comments on the manuscript. Work in the laboratory is funded by the EU, the Deutsche Forschungsgemeinschaft (including SFB 596, 870 and SPP 1356), the German Federal Ministry of Education and Research (BMBF), the Helmholtz Association (CoReNe; Helma), the Fidelity Foundation and ForNeuroCell of the Bavarian State Ministery of Science, Research and Arts.

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  1. Physiological Genomics, Ludwig-Maximilians University of Munich, Germany; and Institute of Stem Cell Research, Helmholtz Center Munich, Germany.

    • Stefanie Robel
    • , Benedikt Berninger
    •  & Magdalena Götz

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Magdalena Götz.

Glossary

Ependymoglia or tanycytes

Radial glia-like cells lining the ventricular surface found in most bony fish and many amphibians that lack differentiated astrocytes and ependymal cells.

Macroglial cells

Glia of neuroectodermal origin, including astrocytes, NG2 cells, oligodendrocytes and ependymal cells.

Oligodendrocyte progenitor cell

A progenitor of the oligodendroglial lineage giving rise to mature oligodendrocytes and NG2 glia.

Tripartite synapse

A concept of synapse physiology appreciating the role of astrocytes in synaptic transmission. It is composed of the pre- and postsynaptic neuronal terminal, as well as astrocytic processes enwrapping these structures.

Glial fibrillary acidic protein

(Often abbreviated to GFAP.) An intermediate filament, which is expressed in astroglia — depending on the subtype and developmental stage — and is strongly upregulated during astrogliosis.

Neurosphere

A clonal aggregate derived from a single cell. It can be propagated for several passages giving rise to further neurospheres, indicative of stem cell self-renewal, and can be differentiated into the main neural lineages, such as neurons, astroglia and oligodendroglia, indicative of multipotency.

Microglia

Glia of mesodermal origin, and the resident macrophages of the CNS.

GLAST::CREERT2

A genetic fate mapping construct for targeting of the tamoxifen-inducible form of the CRE recombinase (CREERT2) to the locus of the astrocyte-specific glutamate transporter GLAST.

Hypertrophy

Reaction of glia to injury characterized by swelling of the cell body and the main processes.

Basement membrane

A specialized sheet-like structure of the extracellular matrix around blood vessels, capillaries and underneath the meninges. Astrocytes, meningeal cells and/or endothelial cells are involved in the generation of the basement membrane within the brain parenchyma.

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https://doi.org/10.1038/nrn2978

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