Not everything is scary about a glial scar

After spinal-cord injury, cells called astrocytes form a scar that is thought to block neuronal regeneration. The finding that the scar promotes regrowth of long nerve projections called axons challenges this long-held dogma. See Article p.195

It has long been a mystery why neurons in the peripheral nervous system can regenerate long projections called axons following injury, whereas neurons in the central nervous system (CNS) cannot1. One difference is that injured CNS axons lose their intrinsic ability to regrow, but studies have also implicated differences in non-neuronal cells called glia1,2, which surround neurons to support them and provide insulation. Damaged glia in the CNS release inhibitors of axon regeneration1, and reactive CNS astrocytes — a type of activated glial cell found at the damaged site — also seem to be powerfully inhibitory3. Research1,2,3 into spinal-cord injury has centred mostly on the consequences of removing or inhibiting development of the reactive-astrocyte scar. It thus comes as a surprise that Anderson et al.4, on page 195 of this issue, find that this scar in fact strongly supports axon regeneration after spinal-cord injury.

Several studies5,6,7,8 in which reactive astrocytes were ablated following stroke and spinal-cord injury have shown that the glial scar has a beneficial role in reducing inflammation and secondary tissue damage, and in promoting the recovery of neuronal activity. These findings seem at odds with a previous study indicating that reactive astrocytes inhibit axon regeneration3 (Fig. 1a). However, this latter study was largely correlational, because it did not directly manipulate reactive astrocytes.

Figure 1: A model of neuronal regrowth.

a, Spinal-cord injury damages neurons, which causes long neuronal projections called axons to die back. Injury also activates non-neuronal cells called astrocytes that, along with fibroblast cells, form a scar. It has long been thought that the astrocytic scar inhibits axon regeneration following injury, thus preventing recovery. b, However, Anderson et al.4 show that removal of the astrocytic scar does not induce axon regrowth, but instead promotes dieback. c, The presence of the scar, when combined with injection of a gel containing growth-promoting factors into the fibrotic scar, actually promotes regrowth in mice.

Anderson et al. set out to directly test the role of reactive astrocytes in axon regeneration following experimental spinal-cord injury, in which axons die and retract. In their first set of experiments, the authors prevented the formation of reactive astrocytes using two genetically modified mouse models to ablate or attenuate the glial scar — in the first model, proliferating scar-forming astrocytes were selectively killed5, and in the second, the transcription factor STAT3 (which is required for formation of scar-forming reactive astrocytes) was deleted in astrocytes. In both cases, the researchers found that spontaneous regrowth of damaged axons through the scar did not occur. In addition, animals lacking the scar showed greater dieback of axons from the injury site than was seen in injured wild-type animals, suggesting that reactive astrocytes actually support injured neurons (Fig. 1b).

In a second set of experiments, Anderson et al. genetically altered astrocytes to express a receptor for diphtheria toxin, before injuring the spinal cord and allowing a scar to form for five weeks. The researchers then ablated the scar by killing astrocytes with ultralow doses of diphtheria toxin. Again, axons failed to regrow through regions depleted of reactive astrocytes. Moreover, the authors observed pronounced tissue degeneration and found that a larger area contained no axons in the astrocyte-scar-free injuries than under control injury conditions. These data demonstrate that, rather than being detrimental to neuronal health and regenerative capacity, the chronic astrocyte scar is crucial for sustained tissue integrity — upending the long-held dogma.

If reactive astrocytes are inhibitory as previously reported3, might they exert this effect by altering the extracellular environment to inhibit axon regrowth, for example by upregulating molecules called chondroitin sulfate proteoglycans (CSPGs) that inhibit growth? Anderson et al. show that levels of such CSPGs are indeed significantly higher in the injured spinal cord than in the same region of control, uninjured animals. But, surprisingly, when the scar was removed, CSPG levels did not fall, and growth-promoting CSPGs were also upregulated in scar-forming astrocytes. Moreover, aggrecan — a classic growth-inhibitory CSPG used in cell-culture experiments as a measure of reactive-astrocyte inhibition of axon regrowth — was not detected in scar-forming astrocytes. Thus, the glial scar is not the primary source of inhibitory CSPGs, quashing another theory.

Axons do not grow by default, but rely on external stimulatory growth cues. Anderson et al. next injected a gel containing growth-promoting factors (the neurotrophins NT3 and BDNF) into the injury site to activate neuronal growth programs. This stimulated axons to robustly regrow directly through the dense astrocytic scar tissue (Fig. 1c). In fact, the authors found axons growing along reactive astrocytes. When the scar was removed, neurotrophins alone did not foster axon regrowth. Taken together, these data provide powerful evidence that astrocyte-scar formation aids, rather than inhibits, axon regeneration after injury.

How can these findings be squared with previous studies suggesting that the glial scar is strongly inhibitory? For one thing, other inhibitory cell types, such as fibroblasts and pericytes9, also contribute to the glial scar. In addition, one study10 has identified different types of reactive astrocyte. It is therefore possible that, in previous studies, different types of injury produced different types of reactive astrocyte, with some types being inhibitory and others not.

Going forward, it will be important to define the signalling mechanisms that induce activation of the different types of reactive astrocyte. Studies of each cell type should then define their functions, whether they can inhibit axon growth and the molecular mechanisms that underlie their roles. This knowledge could enable the selective manipulation of certain astrocytes by specific molecules, which is preferable to deleting an entire cell population that may well both promote and inhibit axon regrowth. In any case, Anderson and colleagues have shown that, in spite of long-held beliefs to the contrary, reactive astrocytes may not be the villains of spinal-cord recovery, but instead might provide new hope for the regeneration of damaged axons.Footnote 1


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Correspondence to Shane A. Liddelow or Ben A. Barres.

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Liddelow, S., Barres, B. Not everything is scary about a glial scar. Nature 532, 182–183 (2016).

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