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Elaine C. Johnson, Thomas A. Doser, Dagnie C. Howard, Madden E. Rowell, William O. Cepurna, John C. Morrison; Mitotic Cells and Astrocyte Precursors in Glaucoma Model Optic Nerve Heads. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2441.
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© ARVO (1962-2015); The Authors (2016-present)
Chronic exposure to elevated intraocular pressure (IOP) produces progressive optic nerve axon degeneration in rat eyes. In the optic nerve head (ONH), this loss is correlated with increased neural volume, increased DNA content and the expression of cell proliferation-associated genes. Here, cell-type specific responses within the ONH are quantified.
Episcleral vein injection of hypertonic saline was used to elevate IOP in rat eyes. At 5 weeks post-injection, optic nerves were graded for injury on a scale ranging from 1 (normal) to 5, ~12% axon loss per unit. Histochemistry, immunolabeling and image analysis were used for nuclear and protein quantification. Statistical analysis utilized linear regression and ANOVA [control, early injury (1<grade<2.5) and advanced injury (grade >2.5) glaucoma model groups].
ONH nuclear density increased linearly with increasing injury grade (r2=0.48, p<0.0001), with a peak in mitotic (KI67+) nuclei at about 10% of the total in the early injury group (Table 1). GFAP+ and AQP4+ areas (differentiated astrocytes) decreased in proportion to injury (r2>0.53, p<0.0001). In contrast, nuclear positivity for PAX2, a transcription factor indicating astrocyte lineage in the ONH, increased (r2=0.64, p<0.0001), resulting in 66% PAX2+ nuclei in advanced injury compared to 46% in controls. Microglia/macrophage nuclei (AIF1+) were significantly increased in density in the advanced group and were activated (Cd68+) in proportion to nerve injury (r2=0.38, p<0.001).
Exposure to elevated IOP leads cellular mitosis and a substantial increase in cellular density within the expanding ONH. While microglia/macrophages are activated and become more abundant, astrocytes dedifferentiate and astrocyte lineage (Pax2+) nuclei increase dramatically in density, implying astrocytic proliferation. These data implicate disrupted functional interactions between astrocytes and the axonal and vascular components of the ONH early in glaucomatous injury.
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