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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.

SUBMITTER: Shafqat A

PROVIDER: S-EPMC10244598 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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

Shafqat Areez A Albalkhi Ibrahem I Magableh Hamzah M HM Saleh Tariq T Alkattan Khaled K Yaqinuddin Ahmed A

Frontiers in cellular neuroscience 20230524

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 sug ...[more]

PMID: 37293626

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Project description:The inflammatory response in the injured spinal cord, an immune privileged site, has been mainly associated with the poor prognosis. However, recent data demonstrated that, in fact, some leukocytes, namely monocytes, are pivotal for repair due to their alternative anti-inflammatory phenotype. Given the pro-inflammatory milieu within the traumatized spinal cord, known to skew monocytes towards a classical phenotype, a pertinent question is how parenchymal-invading monocytes acquire resolving properties essential for healing, under such unfavorable conditions. In light of the spatial association between resolving (interleukin (IL)-10 producing) monocytes and the glial scar matrix chondroitin sulfate proteoglycan (CSPG), in this study we examined the mutual relationship between these two components. By inhibiting the de novo production of CSPG following spinal cord injury, we demonstrated that this extracellular matrix, mainly known for its ability to inhibit axonal growth, serves as a critical template skewing the entering monocytes towards the resolving phenotype. In vitro cell culture studies demonstrated that this matrix alone is sufficient to induce such monocyte polarization. Reciprocal conditional ablation of the monocyte-derived macrophages concentrated at the lesion margins, using diphtheria toxin, revealed that these cells have scar matrix-resolving properties. Replenishment of monocytic cell populations to the ablated mice demonstrated that this extracellular remodeling ability of the infiltrating monocytes requires their expression of the matrix-degrading enzyme, matrix metalloproteinase 13 (MMP-13), a property that was found here to be crucial for functional recovery. Altogether, this study demonstrates that the glial scar-matrix, a known obstacle to regeneration, is a critical component skewing the encountering monocytes towards a resolving phenotype. In an apparent feedback loop, monocytes were found to regulate scar resolution. This cross-regulation between the glial scar and monocytes primes the resolution of this interim phase of spinal cord repair, thereby providing a fundamental platform for the dynamic healing response.

Project description:Regeneration after spinal cord injury (SCI) is limited by the presence of a glial scar and inhibitory cell signaling pathways that favor scar formation over regrowth of endogenous neurons. Tissue engineering techniques, including the use of allografted neural networks, have shown promise for nervous system repair in prior studies. Through the use of a minimally invasive injury model in rats, we describe the implantation of micro-tissue engineered neural networks (micro-TENNs) across a region of SCI, spanning the glial scar to promote axonal regeneration. Forty-three female Sprague-Dawley rats were included in this study. Micro-TENNs were preformed in vitro before implant, and comprised rat sensory dorsal root ganglion (DRG) neurons projecting long bundled axonal tracts within the lumen of a biocompatible hydrogel columnar encasement (1.2 cm long; 701 μm outer diameter × 300 μm inner diameter). Animals were injured using a 2F embolectomy catheter inflated within the epidural space. After a 2-week recovery period, micro-TENNs were stereotactically implanted across the injury. Animals were euthanized at 1 week and 1 month after implantation, and the tissue was interrogated for the survival of graft DRG neurons and outgrowth of axons. No intraoperative deaths were noted with implantation of the micro-TENNs to span the injury cavity. Graft DRG axons were found to survive at 1 week postimplant within the hydrogel encasement. Graft-derived axonal outgrowth was observed within the spinal cord up to 4.5 mm from the implant site at 1 month postinjury. Limited astroglial response was noted within the host, suggesting minimal trauma and scar formation in response to the graft. Micro-TENN sensory neurons survive and extend axons into the host spinal cord following a minimally invasive SCI in rats. This work serves as the foundation for future studies investigating the use of micro-TENNs as a living bridge to promote recovery following SCI. Impact statement As spinal cord injury pathology develops, the establishment of a glial scar puts an end to the hope of regeneration and recovery from the consequent neurological deficits. Therefore, growing attention is given to bioengineered scaffolds that can bridge the lesions bordered by this scar tissue. The utilization of longitudinally aligned preformed neural networks-referred to as micro-tissue engineered neural networks (TENNs)-presents a promising opportunity to provide a multipurpose bridging strategy that may take advantage of several potential mechanisms of host regeneration. In addition to providing physical support for regenerating spinal cord axons, micro-TENNs may serve as a functional "cable" that restores lost connections within the spinal cord.

Project description:After spinal cord injury (SCI), neutrophil elastase (NE) released at injury site disrupts vascular endothelium integrity and stabilization. Angiopoietins (ANGPTs) are vascular growth factors that play an important role in vascular stabilization. We hypothesized that neutrophil elastase is one of the key determinants of vascular endothelium disruption/destabilization and affects angiopoietins expression after spinal cord injury. To test this, tubule formation and angiopoietins expression were assessed in endothelial cells exposed to different concentrations of recombinant neutropil elastase. Then, the expression of angiopoietin-1, angiopoietin-2, and neutrophil elastase was determined at 3 h and at 1, 3, 5, 7, 14, 21, and 28 days in a clinically relevant model of moderate compression (35 g for 5 min at T10) spinal cord injury. A dichotomy between the levels of angiopoietin-1 and angiopoietin-2 was observed; thus, we utilized a specific neutrophil elastase inhibitor (sivelestat sodium; 30 mg/kg, i.p., b.i.d.) after spinal cord injury. The expression levels of neutropil elastase and angiopoietin-2 increased, and that of angiopoietin-1 decreased after spinal cord injury in rats. The sivelestat regimen, optimized via a pharmacokinetics study, had potent effects on vascular stabilization by upregulating angiopoietin-1 via the AKT pathway and preventing tight junction protein degradation. Moreover, sivelestat attenuated the levels of inflammatory cytokines and chemokines after spinal cord injury and hence subsequently alleviated secondary damage observed as a reduction in glial scar formation and the promotion of blood vessel formation and stabilization. As a result, hindlimb locomotor function significantly recovered in the sivelestat-treated animals as determined by the Basso, Beattie, and Bresnahan scale and footprint analyses. Furthermore, sivelestat treatment attenuated neuropathic pain as assessed by responses to von Frey filaments after spinal cord injury. Thus, our result suggests that inhibiting neutropil elastase by administration of sivelestat is a promising therapeutic strategy to inhibit glial scar and promote functional recovery by upregulating angiopoietin-1 after spinal cord injury.

Dataset Information

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

Publications

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

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