Tackling the glial scar in spinal cord regeneration: new discoveries and future directions

Front. Cell. Neurosci., 2023 · DOI: 10.3389/fncel.2023.1180825 · Published: May 24, 2023

Simple Explanation

Following a spinal cord injury (SCI), the body attempts to restore homeostasis, but in the central nervous system (CNS), this process results in scar formation, hindering regeneration. Contemporary research is shifting towards neuron-intrinsic properties, achieving unprecedented neural regeneration through neural stem cell transplantation and neurotrophic factors. The glial scar, traditionally viewed negatively, is now recognized for its dual role: acutely beneﬁcial for damage containment but chronically detrimental to regeneration due to extracellular inhibitors and pro-inﬂammatory signatures. Effective therapeutic strategies must target these processes without compromising neuroprotection. Recent research advocates dividing the SCI scar into three compartments: the inner ﬁbrotic scar, the surrounding astroglial border (or glial scar), and the adjacent reactive neural parenchyma. These compartments exhibit unique cellular compositions and transcriptional proﬁles.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review Article

Key Findings

1
The SCI scar plays both beneficial and harmful roles in SCI, being acutely beneficial for damage containment but chronically contributing to regeneration failure.
2
Spinal cord regenerative capacity varies considerably between embryonic and post-natal life, with older patients displaying poorer neurologic outcomes after SCI.
3
Microglia are crucial for forming a dense astrocytic scar, and attenuating microglial functions can "loosen" the astrocyte scar to allow for axonal regrowth.

Research Summary

This review explores the dual roles of the SCI scar, recognizing its acute benefits in damage control and chronic drawbacks as an impediment to regeneration. It highlights that indiscriminate targeting of the scar's cellular components is detrimental, while more specific and milder interventions can enhance axonal regeneration and functional recovery. The study also underscores the cellular heterogeneity within the SCI scar, emphasizing the importance of cell- and context-specific therapeutic approaches. It calls for further research into the regulation and functional significance of this cellular heterogeneity to develop more targeted treatments. The review suggests future research should focus on the fibrotic core's therapeutic value, the origin of stromal cells, their heterogeneity at the lesion site, and the effects of milder manipulations of stromal cells. It also advocates for exploring the impact of biological aging hallmarks, such as cellular senescence, on SCI responses.

Practical Implications

Targeted Therapies Development

Develop cell- and context-specific therapeutic strategies to address the cellular heterogeneity of the SCI scar.

Fibrotic Core Research

Investigate the therapeutic potential of the fibrotic core, the origin of stromal cells, and the effects of milder manipulations of stromal cells.

Senescence Impact

Explore the impact of biological aging hallmarks such as cellular senescence to improve SCI outcomes.

Study Limitations

1
Lack of specific markers for microglia, OPCs and fibroblasts.
2
Divergent outcomes from different timings of microglial depletion.
3
Technological advancements enabling the examination of microglial heterogeneity at the single-cell level, the upstream regulators and functional consequences of this diversity remain unclear.

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