scholarly journals Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury

2002 ◽  
Vol 159 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Caroline Pot ◽  
Marjo Simonen ◽  
Oliver Weinmann ◽  
Lisa Schnell ◽  
Franziska Christ ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Neurite Growth ◽  
Sciatic Nerve Crush ◽  
Nerve Crush ◽  
Transgenic Expression ◽  
Growth Inhibitory ◽  
Brain And Spinal Cord

Înjured axons in mammalian peripheral nerves often regenerate successfully over long distances, in contrast to axons in the brain and spinal cord (CNS). Neurite growth-inhibitory proteins, including the recently cloned membrane protein Nogo-A, are enriched in the CNS, in particular in myelin. Nogo-A is not detectable in peripheral nerve myelin. Using regulated transgenic expression of Nogo-A in peripheral nerve Schwann cells, we show that axonal regeneration and functional recovery are impaired after a sciatic nerve crush. Nogo-A thus overrides the growth-permissive and -promoting effects of the lesioned peripheral nerve, demonstrating its in vivo potency as an inhibitor of axonal regeneration.

scholarly journals Upregulated lncARAT in Schwann cells promotes axonal regeneration through recruiting macrophages and inducing macrophages M2 polarization

2021 ◽  
Author(s):  
Gang Yin ◽  
Yaofa Lin ◽  
Peilin Wang ◽  
Jun Zhou ◽  
Haodong Lin
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Noncoding Rna ◽  
Macrophage Polarization ◽  
Nerve Repair ◽  
M2 Polarization ◽  
Sciatic Nerves

Abstract BackgroundAxonal regeneration following peripheral nerve injury largely depends on a favorable microenvironment. Schwann cells (SCs) play a crucial role in axonal regeneration by interacting with macrophages, but the mechanisms underlying macrophages recruitment and polarization remain unclear.MethodsThe total RNA of crushed sciatic nerves and intact contralateral nerves was extracted and used to RNA-sequencing (RNA-seq). The differentially expressed long noncoding RNA (lncRNA) and mRNAs were analyzed using bioinformatics analysis, and were verified using qPCR and western blot analysis. The putative role of lncRNA in nerve regeneration was analyzed in vitro and in vivo. Macrophage polarization phenotype was identified by assessing IL-10, Arg-1, and CD206.ResultsHere we identified an lncRNA, termed Axon Regeneration-Associated Transcript (lncARAT), upregulated in SCs and SCs-derived exosomes after crushed sciatic nerves (CSN). LncARAT contributed to axonal regeneration and improved motor functional recovery. Mechanistically, lncARAT epigenetically activated CCL2 expression by recruiting KMT2A to CCL2 promoter, which resulted in an increased H3K4 trimethylation and CCL2 transcription in SCs. CCL2 upregulation facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. Once in macrophage, lncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p, resulting in an increased SOCS2 expression, which facilitated macrophage M2 polarization through a STAT1/6-dependent pathway, thus promoted axonal regeneration.ConclusionsLncARAT may serve as a promising therapeutic avenue for peripheral nerve repair.

scholarly journals LncRNA BC083743 Promotes the Proliferation of Schwann Cells and Axon Regeneration Through miR-103-3p/BDNF After Sciatic Nerve Crush

2020 ◽  
Vol 79 (10) ◽  
pp. 1100-1114
Author(s):  
Lin Gao ◽  
Aiqin Feng ◽  
Peijian Yue ◽  
Yue Liu ◽  
Qiaoyu Zhou ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Schwann Cells ◽  
Axon Regeneration ◽  
Underlying Mechanism ◽  
Regulation Mechanism ◽  
Sciatic Nerve Crush ◽  
Bdnf Expression ◽  
Nerve Crush

Abstract To investigate the underlying mechanism of lncRNA BC083743 in regulating the proliferation of Schwann cells (SCs) and axon regeneration after sciatic nerve crush (SNC), we used a rat model. Sciatic function index and the atrophy ratio of gastrocnemius muscle were evaluated. The relationship among BC083743, miR-103-3p, and brain-derived neurotrophic factor (BDNF) and their regulation mechanism in the repair of SNC were investigated using in vivo and in vitro experiments. The expression changes of BC083743 were positively associated with that of BDNF following SNC, but the expression changes of miR-103-3p were inversely associated with that of BDNF. The SC proliferation and BDNF expression could be promoted by overexpression of BC083743, while they were inhibited by a miR-103-3p mimic. In addition, BC083743 interacted with and regulated miR-103-3p, thereby promoting BDNF expression and SC proliferation. BC083743 overexpression also promoted axon regeneration through miR-103-3p. In vivo experiments also indicated that BC083743 overexpression promoted the repair of SNC. In conclusion, LncRNA BC083743 promotes SC proliferation and the axon regeneration through miR-103-3p/BDNF after SNC.

scholarly journals Upregulated lncARAT in Schwann Cells Promotes Axonal Regeneration through Recruiting Macrophages and Inducing Macrophages M2 Polarization

2021 ◽  
Author(s):  
Gang Yin ◽  
Yaofa Lin ◽  
Peilin Wang ◽  
Jun Zhou ◽  
Haodong Lin
Keyword(s):  
Peripheral Nerve ◽  
Schwann Cells ◽  
Axonal Regeneration ◽  
Noncoding Rna ◽  
Macrophage Polarization ◽  
Nerve Repair ◽  
M2 Polarization ◽  
Sciatic Nerves

Abstract Background: Axonal regeneration following peripheral nerve injury largely depends on a favorable microenvironment. Schwann cells (SCs) play a crucial role in axonal regeneration by interacting with macrophages, but the mechanisms underlying macrophages recruitment and polarization remain unclear. Methods: The total RNA of crushed sciatic nerves and intact contralateral nerves was extracted and used to RNA-sequencing (RNA-seq). The differentially expressed long noncoding RNA (lncRNA) and mRNAs were analyzed using bioinformatics analysis, and were verified using qPCR and western blot analysis. The putative role of lncRNA in nerve regeneration was analyzed in vitro and in vivo. Macrophage polarization phenotype was identified by assessing IL-10, Arg-1, and CD206.Results: Here we identified an lncRNA, termed Axon Regeneration-Associated Transcript (lncARAT), upregulated in SCs and SCs-derived exosomes after crushed sciatic nerves (CSN). LncARAT contributed to axonal regeneration and improved motor functional recovery. Mechanistically, lncARAT epigenetically activated CCL2 expression by recruiting KMT2A to CCL2 promoter, which resulted in an increased H3K4 trimethylation and CCL2 transcription in SCs. CCL2 upregulation facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. Once in macrophage, lncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p, resulting in an increased SOCS2 expression, which facilitated macrophage M2 polarization through a STAT1/6-dependent pathway, thus promoted axonal regeneration. Conclusions: LncARAT may serve as a promising therapeutic avenue for peripheral nerve repair.

scholarly journals Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve

2016 ◽  
Vol 2 ◽  
pp. 205521731664170 ◽  
Author(s):  
Melissa M Gresle ◽  
Yaou Liu ◽  
Trevor J Kilpatrick ◽  
Dennis Kemper ◽  
Qi-Zhu Wu ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Axonal Regeneration ◽  
Antibody Therapy ◽  
Experimental Models ◽  
Therapeutic Effects ◽  
Axonal Loss ◽  
Nerve Crush ◽  
Acute Optic Neuritis ◽  
Injury Models

Background Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. Objective In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. Methods The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. Results In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. Conclusion These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.

scholarly journals Laminin γ1 is critical for Schwann cell differentiation, axon myelination, and regeneration in the peripheral nerve

2003 ◽  
Vol 163 (4) ◽  
pp. 889-899 ◽  
Author(s):  
Zu-Lin Chen ◽  
Sidney Strickland
Keyword(s):  
Schwann Cells ◽  
Peripheral Nerves ◽  
Matrix Proteins ◽  
Myelin Proteins ◽  
Sciatic Nerve Crush ◽  
Similar Reduction ◽  
Nerve Crush ◽  
And Function ◽  
Schwann Cell Differentiation

Laminins are heterotrimeric extracellular matrix proteins that regulate cell viability and function. Laminin-2, composed of α2, β1, and γ1 chains, is a major matrix component of the peripheral nervous system (PNS). To investigate the role of laminin in the PNS, we used the Cre–loxP system to disrupt the laminin γ1 gene in Schwann cells. These mice have dramatically reduced expression of laminin γ1 in Schwann cells, which results in a similar reduction in laminin α2 and β1 chains. These mice exhibit motor defects which lead to hind leg paralysis and tremor. During development, Schwann cells that lack laminin γ1 were present in peripheral nerves, and proliferated and underwent apoptosis similar to control mice. However, they were unable to differentiate and synthesize myelin proteins, and therefore unable to sort and myelinate axons. In mutant mice, after sciatic nerve crush, the axons showed impaired regeneration. These experiments demonstrate that laminin is an essential component for axon myelination and regeneration in the PNS.

scholarly journals Recapitulate development to promote axonal regeneration: good or bad approach?

2006 ◽  
Vol 361 (1473) ◽  
pp. 1565-1574 ◽  
Author(s):  
Marie T Filbin
Keyword(s):  
Spinal Cord ◽  
Axonal Regeneration ◽  
Molecular Level ◽  
Signal Transduction Pathway ◽  
Developmental Changes ◽  
Transduction Pathway ◽  
The Past ◽  
Brain And Spinal Cord ◽  
The Brain

In the past decade there has been an explosion in our understanding, at the molecular level, of why axons in the adult, mammalian central nervous system (CNS) do not spontaneously regenerate while their younger counterparts do. Now a number of inhibitors of axonal regeneration have been described, some of the receptors they interact with to transduce the inhibitory signal are known, as are some of the steps in the signal transduction pathway that is responsible for inhibition. In addition, developmental changes in the environment and in the neurons themselves are also now better understood. This knowledge in turn reveals novel, putative sites for drug development and therapeutic intervention after injury to the brain and spinal cord. The challenge now is to determine which of these putative treatments are the most effective and if they would be better applied in combination rather than alone. In this review I will summarize what we have learnt about these molecules and how they signal. Importantly, I will also describe approches that have been shown to block inhibitors and encourage regeneration in vivo . I will also speculate on what the differences are between the neonatal and adult CNS that allow the former to regenerate and the latter not to.

scholarly journals Non-viral Vector Mediated RNA Interference Technology for Central Nervous System Injury

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Christian Macks ◽  
Jeoung Soo Lee
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rna Interference ◽  
Axonal Regeneration ◽  
Viral Vector ◽  
Traumatic Injury ◽  
Neurite Growth ◽  
Cns Injury ◽  
Growth Inhibitory ◽  
Inhibitory Molecules

AbstractNeuronal axons damaged by traumatic injury are unable to spontaneously regenerate in the mammalian adult central nervous system (CNS), causing permanent motor, sensory, and cognitive deficits. Regenerative failure in the adult CNS results from a complex pathology presenting multiple barriers, both the presence of growth inhibitors in the extrinsic microenvironment and intrinsic deficiencies in neuronal biochemistry, to axonal regeneration and functional recovery. There are many strategies for axonal regeneration after CNS injury including antagonism of growth-inhibitory molecules and their receptors, manipulation of cyclic nucleotide levels, and delivery of growth-promoting stimuli through cell transplantation and neurotrophic factor delivery. While all of these approaches have achieved varying degrees of improvement in plasticity, regeneration, and function, there is no clinically effective therapy for CNS injury. RNA interference technology offers strategies for improving regeneration by overcoming the aspects of the injured CNS environment that inhibit neurite growth. This occurs through the knockdown of growth-inhibitory molecules and their receptors. In this review, we discuss the current state of RNAi strategies for the treatment of CNS injury based on non-viral vector mediated delivery.

scholarly journals Reduced Renshaw Recurrent Inhibition after Neonatal Sciatic Nerve Crush in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-11
Author(s):  
Liang Shu ◽  
Jingjing Su ◽  
Lingyan Jing ◽  
Ying Huang ◽  
Yu Di ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Recurrent Inhibition ◽  
Crush Injury ◽  
Sciatic Nerve Crush ◽  
Nerve Crush ◽  
Nerve Crush Injury

Renshaw recurrent inhibition (RI) plays an important gated role in spinal motion circuit. Peripheral nerve injury is a common disease in clinic. Our current research was designed to investigate the change of the recurrent inhibitory function in the spinal cord after the peripheral nerve crush injury in neonatal rat. Sciatic nerve crush was performed on 5-day-old rat puppies and the recurrent inhibition between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSR) elicited from the sectioned dorsal roots and recorded either from the LG-S and MG nerves by antidromic stimulation of the synergist muscle nerve. Our results demonstrated that the MSR recorded from both LG-S or MG nerves had larger amplitude and longer latency after neonatal sciatic nerve crush. The RI in both LG-S and MG motoneuron pools was significantly reduced to virtual loss (15–20% of the normal RI size) even after a long recovery period upto 30 weeks after nerve crush. Further, the degree of the RI reduction after tibial nerve crush was much less than that after sciatic nerve crush indicatig that the neuron-muscle disconnection time is vital to the recovery of the spinal neuronal circuit function during reinnervation. In addition, sciatic nerve crush injury did not cause any spinal motor neuron loss but severally damaged peripheral muscle structure and function. In conclusion, our results suggest that peripheral nerve injury during neonatal early development period would cause a more sever spinal cord inhibitory circuit damage, particularly to the Renshaw recurrent inhibition pathway, which might be the target of neuroregeneration therapy.

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