Molecular mechanisms underlying functional recovery after spinal cord injury

Spinal cord injury (SCI) is considered incurable because axonal regeneration in the central nervous system (CNS) is extremely challenging, due to harsh CNS injury environment and weak intrinsic regeneration capability of CNS neurons. We discovered that neurotrophin-3 (NT3)-loaded chitosan provided an excellent microenvironment to facilitate nerve growth, new neurogenesis, and functional recovery of completely transected spinal cord in rats. To acquire mechanistic insight, we conducted a series of comprehensive transcriptome analyses of spinal cord segments at the lesion site, as well as regions immediately rostral and caudal to the lesion, over a period of 90 days after SCI. Using weighted gene coexpression network analysis (WGCNA), we established gene modules/programs corresponding to various pathological events at different times after SCI. These objective measures of gene module expression also revealed that enhanced new neurogenesis and angiogenesis, and reduced inflammatory responses were keys to conferring the effect of NT3-chitosan on regeneration.

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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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Dopamine Reduced Pyroptosis and Improved Functional Recovery After Spinal Cord Injury

10.21203/rs.3.rs-75427/v1 ◽

2020 ◽

Author(s):

Liulong Zhu ◽

Guoming Ding ◽

Fan He ◽

Maoqiang Li ◽

Wu Jiang

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Functional Recovery ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Neuronal Loss ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Cord Injury

Abstract Background: Neuronal loss, demyelination, and an excessive inflammatory response accompany the pathogenesis of spinal cord injury (SCI). The inflammatory response is promoted by inflammasomes in variety diseases. Dopamine is a neurotransmitter that also functions as a regulator in NLRP3 (nucleotide-binding oligomerization domain-like receptor 3) inflammasome-dependent neuroinflammation. However, the effects and molecular mechanisms underlying the role of dopamine in SCI are little known. Methods:Functional recovery was assessed using Basso Mouse Scale (BMS) and BMS subscore. Histopathologic damage was evaluated by H&E staining. Demyelination was evaluated using immunofluorescence staining of myelin basic protein. Neuronal loss was evaluated by immunochemistry staining of NeuN. Pyroptosis was assessed by flow cytometry, western blot, and cell viability and cytotoxicity assays.Results: This study using mice showed that dopamine was significantly associated with enhanced locomotor recovery after SCI; with a reduction in NLRP3 inflammasome activation, pyroptosis, neuron and myelin loss, and histological changes. In vitro data suggested an association between dopamine and suppressed NLRP3 inflammasome activation and neuronal pyroptosis, and greater survival of neurons. Conclusion: Thus, dopamine may be a novel and effective approach for improving recovery after SCI.

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Targeted Inhibition of STAT3 in Neural Stem Cells Promotes Neuronal Differentiation and Functional Recovery in Rats with Spinal Cord Injury

10.21203/rs.3.rs-17529/v1 ◽

2020 ◽

Author(s):

Tingting Li ◽

xiaoyang zhao ◽

Jing Duan ◽

Shangbin Cui ◽

Kai Zhu ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Neural Stem Cells ◽

Neuronal Differentiation ◽

Functional Recovery ◽

Tissue Repair ◽

Molecular Mechanisms ◽

Control Shrna ◽

Cord Injury

Abstract BackgroundSignal transducer and activator of transcription protein 3 (STAT3) is expressed in neural stem cells (NSCs), and some studies have shown that STAT3 is involved in regulating NSC differentiation. However, the possible molecular mechanism and the role of STAT3 in spinal cord injury (SCI) are unknown. Thus, in the present study, we identified possible molecular mechanisms by which STAT3 regulates NSC differentiation in vitro and investigated the potential therapeutic effect of transplanting STAT3-silenced NSCs in rat SCI models in vivo.MethodsIn vitro, NSCs were divided into the following three groups: control, control shRNA, and STAT3-shRNA lentivirus groups. NSCs in each treatment group were examined for neuronal differentiation via immunofluorescence, and Western blot analysis was used to investigate the possible molecular mechanisms. In vivo, the rats were divided into four groups that underwent laminectomy and complete spinal cord transection accompanied by transplantation of control-shRNA-treated or STAT3-shRNA-treated NSCs at the injured site. Spinal cord-evoked potentials and the Basso-Beattie-Bresnahan score were used to examine functional recovery after SCI. Axonal regeneration and tissue repair were assessed via retrograde tracing using Fluorogold, hematoxylin-eosin staining and immunofluorescence.ResultsKnockdown of STAT3 promoted neuronal differentiation in NSCs and mechanistic target of mammal rapamycin (mTOR) activation in vitro, and transplantation of STAT3-RNAi-treated NSCs enhanced rat functional recovery and tissue repair, as well as neuronal differentiation of the transplanted NSCs in vivo.ConclusionsWe have provided in vitro and in vivo evidence that STAT3 is a negative regulator of NSC neuronal differentiation. Transplantation of STAT3-inhibited NSCs appears to be a promising potential strategy for enhancing the benefit of NSC-mediated regenerative cell therapy for SCI.

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Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates

10.1101/2021.03.06.434049 ◽

2021 ◽

Author(s):

Gaëtan Poulen ◽

Emilie Aloy ◽

Claire M. Bringuier ◽

Nadine Mestre-Francés ◽

Emaëlle V.F. Artus ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Function ◽

Functional Recovery ◽

Nonhuman Primates ◽

Molecular Mechanisms ◽

Critical Role ◽

Post Injury ◽

Function Recovery ◽

Cord Injury

AbstractNo curative treatment is available for any deficits induced by spinal cord injury (SCI). Following injury, microglia undergo highly diverse activation processes, including proliferation, and play a critical role on functional recovery.In a translational objective, we investigated whether a transient pharmacological reduction of microglia proliferation after injury is beneficial for functional recovery after SCI in mice and nonhuman primates. The colony stimulating factor-1 receptor (CSF1R) regulates proliferation, differentiation, and survival of microglia, we thus used an oral administration of GW2580, a CSF1R inhibitor.First, transient post-injury GW2580 administration in mice improves motor function recovery, promotes tissues preservation and/or reorganization (identified by coherent anti-stokes Raman scattering microscopy), and modulates glial reactivity.Second, post-injury GW2580-treatment in nonhuman primates reduces microglia proliferation, improves functional motor function recovery, and promotes tissue protection. Notably, three months after lesion microglia reactivity returned to baseline value.Finally, to initiate the investigation on molecular mechanisms induced by a transient post-SCI GW2580-treatment, we used microglia-specific transcriptomic analysis in mice. Notably, we detected a downregulation in the expression of inflammatory-associated genes and we identified genes that were up-regulated by SCI and further downregulated by the treatment.Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.

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