The Biology of Regeneration Failure and Success After Spinal Cord Injury

Abstract

Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo-entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI.

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

“…The pathophysiology of SCI is complex with immediate primary mechanical injury followed by a cascade of secondary processes including neuroinflammation, ischemia, and excitotoxity that exacerbate SCI damage [1].…”

Scar Tissue‐Targeting Polymer Micelle for Spinal Cord Injury Treatment

“…Thus, a tissue specific anchoring site is in need to achieve an active targeting delivery with higher efficacy. As it is known, the scar tissue occurs soon after SCI and persists for months at lesion tissue . Notably, a tetra‐peptide CAQK was recently reported able to intravenously home to the scar tissue after traumatic brain injury (TBI), due to its affinity to chondroitin sulfate proteoglycans (CSPGs), a major de novo extracellular components after central nervous system injury .…”

“…As it is known, the scar tissue occurs soon after SCI and persists for months at lesion tissue . Notably, a tetra‐peptide CAQK was recently reported able to intravenously home to the scar tissue after traumatic brain injury (TBI), due to its affinity to chondroitin sulfate proteoglycans (CSPGs), a major de novo extracellular components after central nervous system injury . Thus, we hypothesized that a CAQK‐modified nanoparticle could target the scar tissue actively after SCI, making the scar tissue a reservoir for CAQK‐modified nanoparticles and to function as a drug releasing platform thereafter.…”

Concepts toward directing human astroplasticity to promote neuroregeneration

“…However, the extent to which this reaction and extracellular signaling are transformed by specific insults—including traumatic brain and spinal cord injury (SCI) (Burda et al, ; Okada et al, ), ischemic and hemorrhagic stroke (Scimemi, ), neurodegeneration (Ben Haim et al, ), multiple sclerosis (Ponath et al, ), cancer (Guan et al, ), and pathogen‐mediated inflammation (Skaper et al, )—has been difficult to characterize. This obscurity is due in part to astrocytes’ dynamic and diverse transitions between cellular states (Liddelow and Barres, ; Adams and Gallo, ; Tran et al, ), which can have either beneficial or detrimental impact depending on the type and severity of stimuli. The formation of astroglial scars after injury, for example, is a type of state transition reminiscent of fibrosis and comprised of scar astrocytes.…”