Inflammation and Optic Nerve Regeneration

Andereggen, Lukas; Trakhtenberg, Ephraim F.; Yin, Yuqin; Benowitz, Larry I.

doi:10.1002/9781118732748.ch12

Cited by 6 publications

(16 citation statements)

References 99 publications

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“…Other studies have shown that intraocular inflammation also induces substantial levels of optic nerve regeneration and that this effect is mediated in large part by the atypical growth factor oncomodulin (Ocm), which binds to its cognate receptor on RGCs in a cAMP-dependent manner (Kurimoto et al, 2010; Yin et al, 2009; Yin et al, 2006). The combination of Ocm and a cAMP analog (e.g., CPT-cAMP) captures most of the effects of intraocular inflammation on axon growth without the potentially harmful effects of intraocular inflammation, although Ocm/cAMP has only a small effect on cell survival (Andereggen et al, 2015; Yin et al, 2006). Our other recent work has shown that several members of the Kruppel-like transcription factor (KLF) family contribute to the developmental changes in RGCs’ intrinsic capacity to extend axons, and that knock-down of KLF-4 or KLF-9, two developmentally-upregulated suppressors of axon growth, promotes axon regeneration in mature mice (Apara et al, 2017; Moore et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Zinc chelation and Klf9 knockdown cooperatively promote axon regeneration after optic nerve injury

Trakhtenberg

Feng

et al. 2018

Experimental Neurology

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The inability of axons to regenerate over long-distances in the central nervous system (CNS) limits the recovery of sensory, motor, and cognitive functions after various CNS injuries and diseases. Although pre-clinical studies have identified a number of manipulations that stimulate some degree of axon growth after CNS damage, the extent of recovery remains quite limited, emphasizing the need for improved therapies. Here, we used traumatic injury to the mouse optic nerve as a model system to test the effects of combining several treatments that have recently been found to promote axon regeneration without the risks associated with manipulating known tumor suppressors or oncogenes. The treatments tested here include TPEN, a chelator of mobile (free) zinc (Zn); shRNA against the axon growth-suppressing transcription factor Klf9; and the atypical growth factor oncomodulin combined with a cAMP analog. Whereas some combinatorial treatments produced only marginally stronger effects than the individual treatments alone, co-treatment with TPEN and Klf9 knockdown had a substantially stronger effect on axon regeneration than either one alone. This combination also promoted a high level of cell survival at longer time points. Thus, Zn chelation in combination with Klf9 suppression holds therapeutic potential for promoting axon regeneration after optic nerve injury, and may also be effective for treating other CNS injuries and diseases.

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Section: Introductionmentioning

confidence: 99%

Zinc chelation and Klf9 knockdown cooperatively promote axon regeneration after optic nerve injury

Trakhtenberg

Feng

et al. 2018

Experimental Neurology

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“… 10 The fact that phagocytic cells can support axon regeneration by modifying the nonpermissive optic nerve glial environment has been appreciated for many years, 63 – 67 but the potential of posterior segment inflammation to enhance the phagocytic injury response in the optic nerve per se has not been addressed. 9 , 68 We found that IIR enhances the optic nerve phagocytic response to crush injury and produces lipid molecular changes that reflect clearance of myelin and axon debris. This extends current understanding of IIR to include mechanisms extrinsic to RGCs.…”

Section: Discussionmentioning

confidence: 84%

“…IIR is primarily attributed to progrowth gene expression programs in RGCs that interact with an inflammatory infiltrate in the vitreous. 3 , 5 – 7 , 9 , 16 , 60 – 62 Recent evidence suggests that some features of the optic nerve glial environment can also be favorably impacted by IIR, as in the case of remyelination. 10 The fact that phagocytic cells can support axon regeneration by modifying the nonpermissive optic nerve glial environment has been appreciated for many years, 63 – 67 but the potential of posterior segment inflammation to enhance the phagocytic injury response in the optic nerve per se has not been addressed.…”

Section: Discussionmentioning

confidence: 99%

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Optic Nerve Regeneration After Crush Remodels the Injury Site: Molecular Insights From Imaging Mass Spectrometry

Stark¹,

Anderson

Kwong³

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeMammalian central nervous system axons fail to regenerate after injury. Contributing factors include limited intrinsic growth capacity and an inhibitory glial environment. Inflammation-induced optic nerve regeneration (IIR) is thought to boost retinal ganglion cell (RGC) intrinsic growth capacity through progrowth gene expression, but effects on the inhibitory glial environment of the optic nerve are unexplored. To investigate progrowth molecular changes associated with reactive gliosis during IIR, we developed an imaging mass spectrometry (IMS)-based approach that identifies discriminant molecular signals in and around optic nerve crush (ONC) sites.MethodsONC was performed in rats, and IIR was established by intravitreal injection of a yeast cell wall preparation. Optic nerves were collected at various postcrush intervals, and longitudinal sections were analyzed with matrix-assisted laser desorption/ionization (MALDI) IMS and data mining. Immunohistochemistry and confocal microscopy were used to compare discriminant molecular features with cellular features of reactive gliosis.ResultsIIR increased the area of the crush site that was occupied by a dense cellular infiltrate and mass spectral features consistent with lysosome-specific lipids. IIR also increased immunohistochemical labeling for microglia and macrophages. IIR enhanced clearance of lipid sulfatide myelin-associated inhibitors of axon growth and accumulation of simple GM3 gangliosides in a spatial distribution consistent with degradation of plasma membrane from degenerated axons.ConclusionsIIR promotes a robust phagocytic response that improves clearance of myelin and axon debris. This growth-permissive molecular remodeling of the crush injury site extends our current understanding of IIR to include mechanisms extrinsic to the RGC.

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“…Because molecules found to regulate regeneration of RGC axons, such as Pten and Klf7 3,4 , also affect spinal cord regeneration 4,5 , the mechanisms of axonal regeneration may be similar across CNS projection neurons, while the mechanisms of their pathway-finding vary. A number of intracellular and extracellular factors have been discovered to affect axon regeneration (as reviewed elsewhere, e.g., [6][7][8][9][10][11][12] , but even with manipulation of potent tumorigenic factors <1% of axons regenerated the full-length to their post-synaptic targets [13][14][15] . Thus, although stimulating neuronal intrinsic mechanisms of axon regeneration was sufficient for bypassing extracellular inhibitors of axon growth that are associated with the glial scar and myelin (e.g., CSPG, MAG, NogoA, OMgp, Semaphorins) 10,16 , almost all regenerating axons stall growth far before reaching targets in the brain.…”

Section: Introductionmentioning

confidence: 99%

Post-injury born oligodendrocytes integrate into the glial scar and inhibit growth of regenerating axons by premature myelination

Xing

Rheaume

Kim

et al. 2021

Preprint

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The failure of mature central nervous system (CNS) projection neurons to regenerate axons over long distances drastically limits the recovery of functions lost after various CNS injuries and diseases. A major barrier in axon regeneration research is that, in most neurons, the axonal regenerative response to experimental treatments stalls before the axons reach their post-synaptic targets. Here, we tested the hypothesis that premature de novo myelination of the injured axons that are experimentally stimulated to regenerate stalls their growth, even after the glial scar is bypassed. To test this hypothesis, we used single cell RNA-seq (scRNA-seq) and immunohistological analysis to investigate whether post-injury born oligodendrocytes integrate into the glial scar. We also used a multiple sclerosis model of demyelination concurrently with the stimulation of axon regeneration by Pten knockdown (KD) in projection neurons after traumatic optic nerve injury. We found that post-injury born oligodendrocytes integrate into the glial scar, where they are susceptible to the demyelination treatment, which prevented premature myelination, and thereby enhanced Pten KD-stimulated axon regeneration. We also present a website for comparing the gene expression of scRNA-seq-profiled optic nerve oligodendrocytes under physiological and pathophysiological conditions.

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Inflammation and Optic Nerve Regeneration

Cited by 6 publications

References 99 publications

Zinc chelation and Klf9 knockdown cooperatively promote axon regeneration after optic nerve injury

Zinc chelation and Klf9 knockdown cooperatively promote axon regeneration after optic nerve injury

Optic Nerve Regeneration After Crush Remodels the Injury Site: Molecular Insights From Imaging Mass Spectrometry

Post-injury born oligodendrocytes integrate into the glial scar and inhibit growth of regenerating axons by premature myelination

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