Current Advancements in Spinal Cord Injury Research—Glial Scar Formation and Neural Regeneration

Clifford, Tanner; Finkel, Zachary; Rodriguez, Brianna; Joseph, Adelina; Cai, Li

doi:10.3390/cells12060853

Cited by 54 publications

(34 citation statements)

References 155 publications

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“…SCI constitutes a complex tissue injury, resulting in permanent and degenerative damage to the CNS. Following SCI, deleterious cellular processes ensue, including axonal degeneration, neuronal loss, neuroinflammation, reactive gliosis, and scar formation ( Clifford et al, 2023 ). The inability of the adult mammalian CNS to regenerate post-injury is the direct cause of the permanent loss of sensory and motor functions following SCI ( Noristani, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Iridoids rich fraction from Valeriana jatamansi Jones promotes axonal regeneration and motor functional recovery after spinal cord injury through activation of the PI3K/Akt signaling pathway

Wang,

Lu,

Xiao

et al. 2024

Front. Mol. Neurosci.

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Valeriana jatamansi Jones (VJJ), renowned for its extensive history in traditional Chinese medicine and ethnomedicine within China, is prevalently utilized to alleviate ailments such as epigastric distension and pain, gastrointestinal disturbances including food accumulation, diarrhea, and dysentery, as well as insomnia and other diseases. Moreover, the Iridoid-rich fraction derived from Valeriana jatamansi Jones (IRFV) has demonstrated efficacy in facilitating the recuperation of motor functions after spinal cord injury (SCI). This study is aimed to investigate the therapeutic effect of IRFV on SCI and its underlying mechanism. Initially, a rat model of SCI was developed to assess the impact of IRFV on axonal regeneration. Subsequently, employing the PC12 cell model of oxidative damage, the role and mechanism of IRFV in enhancing axonal regeneration were explored using the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway inhibitor LY294002. Ultimately, the same inhibitor was administered to SCI rats to confirm the molecular mechanism through which IRFV promotes axonal regeneration by activating the PI3K/Akt signaling pathway. The results showed that IRFV significantly enhanced motor function recovery, reduced pathological injury, and facilitated axonal regeneration in SCI rats. In vitro experiments revealed that IRFV improved PC12 cell viability, augmented axonal regeneration, and activated the PI3K/Akt signaling pathway. Notably, the inhibition of this pathway negated the therapeutic benefits of IRFV in SCI rats. In conclusion, IRFV promote promotes axonal regeneration and recovery of motor function after SCI through activation of the PI3K/Akt signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Iridoids rich fraction from Valeriana jatamansi Jones promotes axonal regeneration and motor functional recovery after spinal cord injury through activation of the PI3K/Akt signaling pathway

Wang,

Lu,

Xiao

et al. 2024

Front. Mol. Neurosci.

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“…The polarization state and other characteristics of macrophage populations recruited into the injured spinal cord were studied by immunohistochemical analysis [ 66 ]. Previous studies [ 89 , 90 , 91 , 92 , 93 , 94 , 95 ] indicated that in spinal cord injuries, M1 macrophages facilitate phagocytosis and secrete pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). These macrophages perform cell debris clearance, and their persistence can also lead to cell death and axonal dieback through increased reactive oxygen species (ROS) generation.…”

Section: Nerve Regeneration In Injured Spinal Cord By α-Gal Nanoparti...mentioning

confidence: 99%

“…Thus, this treatment enables the localized production of VEGF for several weeks, thereby ensuring prolonged enhancing effects on axonal ingrowth into the lesion. In view of the multiple neurotrophins produced by M2 macrophages [ 18 , 94 , 95 , 96 , 97 , 98 , 99 ], it will be of interest to determine whether the M2 macrophages that mediate axonal regeneration in SCI lesions treated with α-gal nanoparticles also produce these neurotrophins at the injection sites.…”

Section: Nerve Regeneration In Injured Spinal Cord By α-Gal Nanoparti...mentioning

confidence: 99%

Regeneration in Mice of Injured Skin, Heart, and Spinal Cord by α-Gal Nanoparticles Recapitulates Regeneration in Amphibians

Galili,

Li,

Schaer

2024

Nanomaterials

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The healing of skin wounds, myocardial, and spinal cord injuries in salamander, newt, and axolotl amphibians, and in mouse neonates, results in scar-free regeneration, whereas injuries in adult mice heal by fibrosis and scar formation. Although both types of healing are mediated by macrophages, regeneration in these amphibians and in mouse neonates also involves innate activation of the complement system. These differences suggest that localized complement activation in adult mouse injuries might induce regeneration instead of the default fibrosis and scar formation. Localized complement activation is feasible by antigen/antibody interaction between biodegradable nanoparticles presenting α-gal epitopes (α-gal nanoparticles) and the natural anti-Gal antibody which is abundant in humans. Administration of α-gal nanoparticles into injuries of anti-Gal-producing adult mice results in localized complement activation which induces rapid and extensive macrophage recruitment. These macrophages bind anti-Gal-coated α-gal nanoparticles and polarize into M2 pro-regenerative macrophages that orchestrate accelerated scar-free regeneration of skin wounds and regeneration of myocardium injured by myocardial infarction (MI). Furthermore, injection of α-gal nanoparticles into spinal cord injuries of anti-Gal-producing adult mice induces recruitment of M2 macrophages, that mediate extensive angiogenesis and axonal sprouting, which reconnects between proximal and distal severed axons. Thus, α-gal nanoparticle treatment in adult mice mimics physiologic regeneration in amphibians. These studies further suggest that α-gal nanoparticles may be of significance in the treatment of human injuries.

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“…During this injury-induced spike in proliferative activity, NSC progeny migrate towards the injury site, where they continue to proliferate and subsequently differentiate into reactive astrocytes, contributing to the formation of the glial scar (Nicaise et al, 2022), sealing the injury site and limiting secondary injury effects to protect surrounding healthy tissue. The glial scar constitutes a key barrier to outgrowing axons from the injured pathways from reconnecting with their original targets, limiting functional recovery (Bradbury & Burnside, 2019;Clifford et al, 2023;Leal-Filho, 2011;McDonough & Martínez-Cerdeño, 2012;Meletis et al, 2008;Moreno-Manzano, 2020;Nicaise et al, 2022;Tran et al, 2022). Microenvironmental injury sequelae to SCI with compression injuries which leave the dural sack intact, and burst fracture injuries, which induce dural laceration and subsequent intradural decompression, may not be identical.…”

Section: Introductionmentioning

confidence: 99%

In vitrosurvival and neurogenic potential of central canal-derived neural stem cells depend on spinal cord injury type

Schiro,

Bauer,

Bjorkli

et al. 2024

Preprint

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The central canal (CC) of the spinal cord is a neurogenic niche consisting of quiescent neural stem cells (NSCs) capable of responding to traumatic damage to the spinal cord by increasing their proliferative activity and sending migrating progeny toward the site of injury, where they contribute to the formation of the glial scar. However, CC NSCs have been demonstrated to have the capability to differentiate into all neural lineage cells in vitro, but also in vivo, in response to infusion of specific growth factors that promote neuronal induction after injury, as well as when transplanted into other neurogenic niches, such as the subgranular zone of the hippocampus. This suggests that CC NSCs may represent a recruitable endogenous source of neural lineage cells that could be harnessed to replenish damaged or lost neural tissue after traumatic spinal cord injury (SCI). NSCs isolated from the CC neurogenic niche of uninjured rats and mice have been shown to display limited proliferative capacity in vitro, with significantly greater proliferative activity achieved with NSCs isolated from SCI-lesioned rats and mice indicating an injury-specific activation of the quiescent CC NSC pool. A central question that currently remains unanswered is whether, and to what extent the CC niche can spontaneously generate viable neurons, and act as a potential source of new cells to replace lost neuronal populations in situ, and whether SCI sequalae impact future NSC neurogenic potential. To address this question, we need to understand whether the nature of the injury plays a role in the CC neurogenic niche response. In this study, we compared the intrinsic proliferative response and neurogenic potential of NSCs harvested from the CC neurogenic niche in adult female Sprague Dawley rats by culturing said NSCs across three conditions; (i) control, i.e., uninjured tissue, (ii) after in vivo compression injury 3 days before harvesting, and (iii) after in vivo simulated burst fracture injury 3 days before harvesting in vitro. We found that lacerations of the dura mater surrounding the spinal cord during a compression injury resulted in drastically altered and persistent in vitro NSC behavior encompassing both proliferation and development compared to uninjured control and compression injury with the dura intact.

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Current Advancements in Spinal Cord Injury Research—Glial Scar Formation and Neural Regeneration

Cited by 54 publications

References 155 publications

Iridoids rich fraction from Valeriana jatamansi Jones promotes axonal regeneration and motor functional recovery after spinal cord injury through activation of the PI3K/Akt signaling pathway

Iridoids rich fraction from Valeriana jatamansi Jones promotes axonal regeneration and motor functional recovery after spinal cord injury through activation of the PI3K/Akt signaling pathway

Regeneration in Mice of Injured Skin, Heart, and Spinal Cord by α-Gal Nanoparticles Recapitulates Regeneration in Amphibians

In vitrosurvival and neurogenic potential of central canal-derived neural stem cells depend on spinal cord injury type

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