Expressing Constitutively Active Rheb in Adult Neurons after a Complete Spinal Cord Injury Enhances Axonal Regeneration beyond a Chondroitinase-Treated Glial Scar

Object Glial scar and cystic formation greatly contribute to the inhibition of axonal regeneration after spinal cord injury (SCI). Attempts to promote axonal regeneration are extremely challenging in this type of hostile environment. The objective of this study was to examine the surgical methods that may be used to assess the factors that influence the level of scar and cystic formation in SCI. Methods In the first part of this study, a complete transection was performed at vertebral level T9–10 in adult female Sprague-Dawley rats. The dura mater was either left open (control group) or was closed using sutures or hyaluronic acid. In the second part of the study, complete or subpial transection was performed, with the same dural closure technique applied to both groups. Histological analysis of longitudinal sections of the spinal cord was performed, and the percentage of scar and cyst formation was determined. Results Dural closure using sutures resulted in significantly less glial scar formation (p = 0.0248), while incorporation of the subpial transection surgical technique was then shown to significantly decrease cyst formation (p < 0.0001). Conclusions In this study, the authors demonstrated the importance of the vasculature in cyst formation after spinal cord trauma and confirmed the importance of dural closure in reducing glial scar formation.

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Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

Neural Plasticity ◽

10.1155/2016/1279051 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Ping Li ◽

Zhao-Qian Teng ◽

Chang-Mei Liu

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Axon Regeneration ◽

Therapeutic Potential ◽

Glial Scar ◽

Scar Formation ◽

Extrinsic Factors ◽

Cord Injury ◽

The Central Nervous System

Spinal cord injury is a devastating disease which disrupts the connections between the brain and spinal cord, often resulting in the loss of sensory and motor function below the lesion site. Most injured neurons fail to regenerate in the central nervous system after injury. Multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration after injury. MicroRNAs can modulate multiple genes’ expression and are tightly controlled during nerve development or the injury process. Evidence has demonstrated that microRNAs and their signaling pathways play important roles in mediating axon regeneration and glial scar formation after spinal cord injury. This article reviews the role and mechanism of differentially expressed microRNAs in regulating axon regeneration and glial scar formation after spinal cord injury, as well as their therapeutic potential for promoting axonal regeneration and repair of the injured spinal cord.

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Serotonin inhibits axonal regeneration of identifiable descending neurons after a complete spinal cord injury in lampreys

10.1101/335844 ◽

2018 ◽

Author(s):

Daniel Sobrido-Cameán ◽

Diego Robledo ◽

Laura Sánchez ◽

María Celina Rodicio ◽

Antón Barreiro-Iglesias

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Axonal Guidance ◽

Descending Neurons ◽

Expression Of Genes ◽

Subsequent Decrease ◽

Cord Injury ◽

Key Factor ◽

Complete Spinal Cord Injury

SummaryClassical neurotransmitters are mainly known for their roles as neuromodulators, but they also play important roles in the control of developmental and regenerative processes. Here, we used the lamprey model of spinal cord injury to study the effect of serotonin in axon regeneration at the level of individually identifiable descending neurons. Pharmacological and genetic treatments after a complete spinal cord injury showed that endogenous serotonin inhibits axonal regeneration in identifiable descending neurons through the activation of serotonin 1A receptors and a subsequent decrease in cAMP levels. RNA sequencing revealed that changes in the expression of genes that control axonal guidance could be a key factor on the serotonin effects during regeneration. This study provides new targets of interest for research in non-regenerating mammalian models of traumatic CNS injuries and extends the known roles of serotonin signalling during neuronal regeneration.

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Serotonin inhibits axonal regeneration of identifiable descending neurons after a complete spinal cord injury in lampreys

Disease Models & Mechanisms ◽

10.1242/dmm.037085 ◽

2019 ◽

Vol 12 (2) ◽

pp. dmm037085 ◽

Cited By ~ 4

Author(s):

Daniel Sobrido-Cameán ◽

Diego Robledo ◽

Laura Sánchez ◽

María Celina Rodicio ◽

Antón Barreiro-Iglesias

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Descending Neurons ◽

Cord Injury ◽

Complete Spinal Cord Injury

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Taurine promotes axonal regeneration after a complete spinal cord injury in lampreys

10.1101/655191 ◽

2019 ◽

Author(s):

Daniel Sobrido-Cameán ◽

Blanca Fernández-López ◽

Natividad Pereiro ◽

Anunciación Lafuente ◽

María Celina Rodicio ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Axon Regeneration ◽

Traumatic Event ◽

Axonal Regrowth ◽

Cord Injury ◽

Taurine Treatment ◽

Complete Spinal Cord Injury ◽

The Brain

AbstractTaurine is one of the most abundant free amino acids in the brain. It is well known that taurine protects the brain from further damage after a traumatic event. However, only a few ex vivo studies have looked at the possible role of taurine in the regulation of axon regeneration after injury. Here, we aimed to reveal the possible role for taurine in the modulation of axonal regeneration following a complete spinal cord injury (SCI) using lampreys as an animal model. The brainstem of lampreys contains several individually identifiable descending neurons that differ greatly in their capacity for axonal regeneration after SCI. This offers a convenient model to promote or inhibit axonal regrowth in the same in vivo preparation. First, we carried out high performance liquid chromatography experiments to measure taurine levels in the spinal cord following SCI. Our results revealed a statistically significant increase in taurine levels 4 weeks post lesion, which suggested that taurine might have a positive effect on axonal regrowth. Based on these results, we decided to apply an acute taurine treatment at the site of injury to study its effect on axon regeneration. Results from these experiments show that an acute taurine treatment enhances axonal regeneration following SCI in lampreys. This offers a novel way to try to promote axon regeneration after nervous system injuries in mammalian models.

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The Biology of Regeneration Failure and Success After Spinal Cord Injury

Physiological Reviews ◽

10.1152/physrev.00017.2017 ◽

2018 ◽

Vol 98 (2) ◽

pp. 881-917 ◽

Cited By ~ 110

Author(s):

Amanda Phuong Tran ◽

Philippa Mary Warren ◽

Jerry Silver

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Axonal Regeneration ◽

Molecular Mechanisms ◽

Glial Scar ◽

Perineuronal Net ◽

Physical Trauma ◽

Axonal Regrowth ◽

Cord Injury

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.

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Schwann cell transplantation for spinal cord injury repair: its significant therapeutic potential and prospectus

Reviews in the Neurosciences ◽

10.1515/revneuro-2014-0068 ◽

2015 ◽

Vol 26 (2) ◽

Cited By ~ 55

Author(s):

Haruo Kanno ◽

Damien D. Pearse ◽

Hiroshi Ozawa ◽

Eiji Itoi ◽

Mary Bartlett Bunge

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Functional Recovery ◽

Axonal Regeneration ◽

Therapeutic Strategy ◽

Glial Scar ◽

Scar Formation ◽

Tissue Loss ◽

Injured Spinal Cord ◽

Cord Injury

AbstractTransplantation of Schwann cells (SCs) is a promising therapeutic strategy for spinal cord repair. The introduction of SCs into the injured spinal cord has been shown to reduce tissue loss, promote axonal regeneration, and facilitate myelination of axons for improved sensorimotor function. The pathology of spinal cord injury (SCI) comprises multiple processes characterized by extensive cell death, development of a milieu inhibitory to growth, and glial scar formation, which together limits axonal regeneration. Many studies have suggested that significant functional recovery following SCI will not be possible with a single therapeutic strategy. The use of additional approaches with SC transplantation may be needed for successful axonal regeneration and sufficient functional recovery after SCI. An example of such a combination strategy with SC transplantation has been the complementary administration of neuroprotective agents/growth factors, which improves the effect of SCs after SCI. Suspension of SCs in bioactive matrices can also enhance transplanted SC survival and increase their capacity for supporting axonal regeneration in the injured spinal cord. Inhibition of glial scar formation produces a more permissive interface between the SC transplant and host spinal cord for axonal growth. Co-transplantation of SCs and other types of cells such as olfactory ensheathing cells, bone marrow mesenchymal stromal cells, and neural stem cells can be a more effective therapy than transplantation of SCs alone following SCI. This article reviews some of the evidence supporting the combination of SC transplantation with additional strategies for SCI repair and presents a prospectus for achieving better outcomes for persons with SCI.

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Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury

Molecular Therapy ◽

10.1016/j.ymthe.2017.08.011 ◽

2017 ◽

Vol 25 (12) ◽

pp. 2715-2726 ◽

Cited By ~ 11

Author(s):

Di Wu ◽

Michelle C. Klaw ◽

Theresa Connors ◽

Nikolai Kholodilov ◽

Robert E. Burke ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Cervical Spinal Cord ◽

Cervical Spinal Cord Injury ◽

Cord Injury ◽

Constitutively Active

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Genes and miRNAs as Hurdles and Promoters of Corticospinal Tract Regeneration in Spinal Cord Injury

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.748911 ◽

2021 ◽

Vol 9 ◽

Author(s):

Marina Boido ◽

Alessandro Vercelli

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Chronic Phase ◽

Axon Growth ◽

Glial Scar ◽

Neural Regeneration ◽

Axonal Regrowth ◽

Cord Injury ◽

Sensory Motor

Spinal cord injury (SCI) is a devastating lesion to the spinal cord, which determines the interruption of ascending/descending axonal tracts, the loss of supraspinal control of sensory-motor functions below the injured site, and severe autonomic dysfunctions, dramatically impacting the quality of life of the patients. After the acute inflammatory phase, the progressive formation of the astrocytic glial scar characterizes the acute-chronic phase: such scar represents one of the main obstacles to the axonal regeneration that, as known, is very limited in the central nervous system (CNS). Unfortunately, a cure for SCI is still lacking: the current clinical approaches are mainly based on early vertebral column stabilization, anti-inflammatory drug administration, and rehabilitation programs. However, new experimental therapeutic strategies are under investigation, one of which is to stimulate axonal regrowth and bypass the glial scar. One major issue in axonal regrowth consists of the different genetic programs, which characterize axonal development and maturation. Here, we will review the main hurdles that in adulthood limit axonal regeneration after SCI, describing the key genes, transcription factors, and miRNAs involved in these processes (seen their reciprocal influencing action), with particular attention to corticospinal motor neurons located in the sensory-motor cortex and subjected to axotomy in case of SCI. We will highlight the functional complexity of the neural regeneration programs. We will also discuss if specific axon growth programs, that undergo a physiological downregulation during CNS development, could be reactivated after a spinal cord trauma to sustain regrowth, representing a new potential therapeutic approach.

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