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Jie Ma, Chenying Guo, Caiwei Guo, Tiffany Liao, Ursula Beattie, Gianna Teague, Dongfeng Chen, Kameran Lashkari; Neuroprotective Effects of IGF-1 on Retinal Ganglion Cell Survival. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5739.
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© ARVO (1962-2015); The Authors (2016-present)
We previously found that the neural progenitor cells isolated from human persistent fetal vasculature (hNPPFVs) can differentiate into retinal ganglion-like cells (RGCs) after transplantation into the mouse vitreous. These observations led us to investigate if hNPPFVs would be good candidates to locally delivery neuroprotective factors, such as IGF-1, to the inner retina against stress-induced RGC loss.
IGF-1 cDNA spliced into a double-red fluorescent reporter, tdTomato or tdTomato alone were cloned into pJ603-neo vector and transfected into hNPPFVs to create hNPPFVIGF-1/tdTomato and hNPPFVtdTomato cells. An established bead model of murine glaucoma was created by injecting polystyrene microbeads into the anterior chambers of adult C57BL/6J mice. Animals were intravitrealy injected with 2 μl (~50000 cells) of either hNPPFVIGF-1/tdTomato, hNPPFVtdTomato or hNPPFV cells. IOP was measured every 3 days for 4 weeks after cell transplantation. Whole mount retina and eyecup cross sections were used to quantify RGCs. Expression of Beta-III-tubulin, HLA I and anti-tdTomato was examined in retinal flatmounts and sections. Semi-thin optic nerve cross sections were used for axon quantification.
Bead injection induced an elevation of IOP from baseline of 10 to 25 mmHg in 7 days with a sustained effect up to 4 weeks. At 4 weeks post injection, IOP began to decrease but remained above baseline levels. PBS injection did not cause a sustained IOP elevation and served as controls. RGC density decreased in glaucomatous eyes transplanted with hNPPFVtdTomato or hNPPFV cells (~2500 RGCs/mm2), but remained unchanged in glaucomatous mice redeived hNPPFVIGF-1/tdTomato injection as compared to the control group (Both ~4100 RGCsmm2). Immunohistochemical analysis of serial sections confirmed that significantly more RGC nuclei were lost in hNPPFVtdTomato or hNPPFVs injected eyes vs. hNPPFVIGF-1/tdTomato treated group. Examination of optic nerve cross sections further demonstrated decreased number of axons in hNPPFVtdTomato and hNPPFV vs. hNPPFVIGF-1/tdTomato injected eyes.
Transplantation of hNPPFVIGF-1/tdTomato cells secreting biologically active IGF-1 in a form of fusion protein, IGF-1-tdTomato, improves the survival of RGCs and optic nerve axons in the bead model of murine glaucoma. These findings support the concept of using IGF-1 as a key neuroprotective factor against stress-induced RGC loss and clinical glaucoma.
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