Astrocyte scar formation aids CNS axon regeneration

By Mark A. Anderson, J. Burda, Yilong Ren, Y. Ao, Timothy M. O’Shea, Riki Kawaguchi, G. Coppola, B. Khakh, T. Deming, M. Sofroniew. Nature, 2016

1,581 citations recorded by the source corpus.

Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience

View Paper: https://www.semanticscholar.org/paper/a732691fb339ee98e5b2cf6f627fdb2ab3eb42cc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. Sofroniew
2. A. Tran
3. B. Barres
4. J. Silver
5. P. Warren
6. M. Pekny
7. M. Pekna
8. J. Burda

In Developmental Neuroscience

1. M. Sofroniew
2. C. Farina
3. E. Colombo
4. J. Silver
5. A. Tran
6. B. Barres
7. M. Pekny
8. J. Burda

Citations in the corpus

• Astrocytes: Key Regulators of Neuroinflammation. (2016, background): “deficits, scar disorganization, spreading and persistence of inflammatory cells, BBB alterations, and, when analyzed, demyelination and neuronal death [10–16] (Table 1).”
• The Biology of Regeneration Failure and Success After Spinal Cord Injury. (2018, methodology): “(6), which we believe erroneously interprets that the astrocytic scar always aids axonal regeneration (FIGURE 5C).”
• Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms (2019, background): “From these observations, the authors suggested a positive role for the astrocytic scar in axonal regeneration following SCI (321).”
• Astrocyte reactivity: Subtypes, states and functions in CNS innate immunity (2020, background): “Moreover, recent evidence suggests that reactive astrocytes can contribute to synapse remodeling and circuit reorganization [6, 33, 37], and even the longstanding view that reactive astrocytes are the primary cause for the failure CNS axon regeneration has been overturned [57, 69, 76, 77].”
• Normal aging induces A1-like astrocyte reactivity (2018, background): “This transcription factor is thought to be required for the induction astrocyte gliosis (25, 26).”
• Spinal cord injury: molecular mechanisms and therapeutic interventions (2023, background): “Local astrocytes are activated by inflammatory reactions secondary to SCI and form a narrow astrocyte scar surrounding the fibrotic scar, protecting adjacent spare neural cells.(147,148,173,174) In the distal area of the lesion, continuous with the astrocyte scar, the spare but reactive neural tissu”