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Steven L Bernstein, Yan Guo, Zara Mehrabyan, Candace Kerr, Rebecca J Fawcett, sally Temple, Jeffrey Stern; The optic nerve lamina region (ONLR) contains a neural progenitor/stem cell (NPC/NSC) niche. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6387.
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© ARVO (1962-2015); The Authors (2016-present)
Neural stem/progenitor cell (NSC/NPC) niches display many unique characteristics, including a vascular plexus to monitor and responds to the cells surrounding the niche, expression of multiple stem cell protein markers, ability to generate multiple neural cell types, and age-depletion. We report that the optic nerve laminar region (ONLR) contains a previously suspected NSC/NPC niche, and some of its functions.
WT and transgenic mice strains were on an identical background (C57Bl6/J): Sox2-ER2-Cre animals express Cre recombinase in Sox2 (+) cells only after treatment with Tamoxifen (Tam). ROSA26 td-Tomato-LoxP(GFP) mice express Td-tomato (red), but switch to GFP (green) under cre-based recombination. ROSA26 LoxP(DTA) express diphtheria toxin-A subunit only following Cre-based recombination, resulting in elimination of Sox2 (+) expressing cells. ONLR and distal ON’s were dissected, dissociated and cultures established. Tissues were evaluated in situ using appropriate antibodies to target proteins as indicated. ON ultrastructure was evaluated by transmission electron microscopy (TEM).
Both human and rodent ONLRs contain cells co-expressing the NSC-associated proteins nestin, Sox2, and GFAP in a precise organization, with lack of this pattern in distal ON. These cells decline with age. ONLR-Sox2 expression was not associated with NG2(+) oligodendrocyte progenitor cells (OPCs) residing in the ON. Unlike distal ON cultures, ONLR cultures generated exuberant growth of NPCs that form smooth walled neurospheres on low adherence medium. These cells give rise to NG2(+)/Sox2(+)/GFAP(-) OPCs, astrocytes and occasionally neurons. Early postnatal loss of ONLR-NPCs in vivo resulted in anterior ON hypomyelination, without decreased myelination in the mid-distal ON.
The ONLR contains an age-depletable NPC niche, responsible for postnatal myelination in the anterior ON, as well as maintenance of normal ONLR boundary functions including blockade of intraretinal myelination. ONLR-NPCs can be expanded and grown in culture. ONLR-NPCs are primarily tripotential in nature, giving rise to both astrocytes, occasionally neurons and OPCs, which then generate oligodendrocytes. ONLR-NPC loss results in increased extracellular spacing and anterior ON hypomyelination. ONLR-NPCs likely play a major role in the ability of the ON to resist stressors, and their loss may predispose to ON-specific diseases.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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