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

Stark DT, Anderson DMG, Kwong JMK, Patterson NH, Schey KL, Caprioli RM, Caprioli J
Invest Ophthalmol Vis Sci. 2018 59 (1): 212-222

PMID: 29340649 · PMCID: PMC5770179 · DOI:10.1167/iovs.17-22509

Purpose - Mammalian 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.

Methods - ONC 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.

Results - IIR 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.

Conclusions - IIR 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.

MeSH Terms (17)

Animals Axons Cell Count Cell Survival Disease Models, Animal Gliosis Lipid Metabolism Male Microscopy, Confocal Nerve Crush Nerve Regeneration Neuronal Plasticity Optic Nerve Optic Nerve Injuries Rats Rats, Inbred F344 Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

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