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

Abstract

Axonal regeneration and functional recovery are poor after spinal cord injury (SCI), typified by the formation of an injury scar. While this scar was traditionally believed to be primarily responsible for axonal regeneration failure, current knowledge takes a more holistic approach that considers the intrinsic growth capacity of axons. Targeting the SCI scar has also not reproducibly yielded nearly the same efficacy in animal models compared to these neuron-directed approaches. These results suggest that the major reason behind central nervous system (CNS) regeneration failure is not the injury scar but a failure to stimulate axon growth adequately. These findings raise questions about whether targeting neuroinflammation and glial scarring still constitute viable translational avenues. We provide a comprehensive review of the dual role of neuroinflammation and scarring after SCI and how future research can produce therapeutic strategies targeting the hurdles to axonal regeneration posed by these processes without compromising neuroprotection.

Oligodendrocyte Progenitors in Glial Scar: A Bet on Remyelination

“…Myelin and oligodendrocyte loss start immediately after acute injuries, such as SCI or TBI (i.e., within 15 min and for 24–48 h at the core of the injury), likely due to the combinatorial effects of bleeding, hypoxia, oxidative damage, ATP- and glutamate-mediated excitotoxicity and the release of pro-inflammatory cytokines such as interleukin-1α (IL-1α), and tumour necrosis factor-α (TNF-α) [ 6 , 34 ] ( Figure 1 ). While neurons and astrocytes do not typically die beyond 24 h post-injury, oligodendrocyte apoptosis is instead protracted up to the subacute (i.e., 3–14 days after injury) and chronic phases, especially in distal degenerating axon tracts after SCI [ 35 ].…”

“…Then, over time, the stromal component (i.e., fibroblasts and pericytes) progressively prevails over the blood-derived inflammatory cells and becomes the dominant cell population of the fibrotic scar, being embedded in a rich deposit of extracellular matrix (ECM) [ 3 , 4 ]. Newly generated astrocytes, oligodendrocyte progenitor cells (OPCs, or NG2 glia) and microglia are, instead, the main components of the surrounding ring, the proper glial scar [ 2 , 5 ], whereas the adjacent neural parenchyma comprises neurons actively engaged in neurite and synaptic remodelling [ 6 ].…”

Cellular senescence in brain aging and cognitive decline

“…Cellular heterogeneity at the metabolomic, epigenomic, transcriptomic, and proteomic levels is being increasingly appreciated in astrocytes and microglia (Shafqat et al, 2023). Current consensus from the scientific community advocates moving away from the binary classification of astrocytes and microglia into pro-inflammatory (A1 or M1) and anti-inflammatory (A2 or M2) in favor of a spectrum of glial cell reactivity that ranges between the extremes of pro-inflammatory/ neurotoxic and anti-inflammatory/neuroprotective phenotypes (Escartin et al, 2021;Paolicelli et al, 2022).…”

Physically and Chemically Crosslinked Hyaluronic Acid-Based Hydrogels Differentially Promote Axonal Outgrowth from Neural Tissue Cultures

“…Limited functional recovery after neuronal injury is often associated with poor axonal regeneration. Moreover, massive neuron death that follows the injury also contributes to overall neurological deficit [ 1 , 2 , 3 , 4 ]. Attempts to promote axonal regeneration and neuroprotection both after spinal cord injuries and peripheral nerve injuries have been made by using numerous biomaterials [ 5 , 6 ].…”