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Steven L Bernstein, Zara Mehrabyan, Candace Kerr, Sally Temple, Jeffrey Stern, Yan Guo; The optic nerve lamina is a neural progenitor cell niche. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1385.
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© ARVO (1962-2015); The Authors (2016-present)
The optic nerve (ON) is a myelinated CNS tract connecting the eye and brain, comprised of retinal ganglion cell (RGC) axons. RGC axons are unmyelinated in the retina but are myelinated after traversing the optic nerve lamina (ONL). The reason for this discontinuity is unknown but suggests that the ONL may facilitate this process. One possibility is that the ONL is a source of myelinating progenitor cells. This would be of great significance to a number of ON diseases, including glaucoma, which may originate from problems in the ONL. The ONL has an unusual vascularization distinct from the rest of the ON, in that the ONL receives circulation from the retina, underlying choroid, and intrinsic ON vasculature. Thus, the ONL is uniquely poised in this area to provide a progenitor cell niche. We evaluated the ONL as a potential source for progenitor cells.
Rodent ONL vasculature was mapped using two photon microscopy, and analyzed by gene expression and immunohistochemically for nestin and other neural progenitor genes, myelin components, oligodendrocyte and astrocyte precursors (Olig-1, PDGFRα, NG2), and neuronal proteins. We generated ONL-cell cultures and also utilized two mouse strains (ER-Cre-Nestin and -PDGFRα), crossing them with ROSA26/LoxP mice with enhanced yellow fluorescent protein (EYFP) to localize after progenitor development. Human donor tissues of a variety of ages were analyzed for nestin expression.
Nestin expression strongly localizes to the ONL in the young adult animal, with more differentiated, but still immature NG2+ glial precursors directly behind the ONL. EDU-mitotic labeling reveals mitotic nestin (+) cells with slow turnover. ER-Cre-PDGFR X ROSA double heterozygous mice demonstrated EYFP oligodendrocytes banding directly under the ONL, in the anterior ON. The ONL expresses genes for early neuronal, as well as glial function. ONL-nestin expression declines during both human and rodent aging, with a near absence in humans over 60y of age.
The ONL is a progenitor cell niche. This niche may aid directionality of myelination/myelin barrier function, function for necessary replacement of glial cells in the highly stressful environment of the eye-nerve junction, and may generate post-embryonic retinal neurons. The loss of the ONL progenitor niche may play a key role in the progression of intrinsic ON diseases such as glaucoma, where current treatment options are of limited usefulness.
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