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H. Levkovitch-Verbin, O. Sadan, S. Vander, Y. Barhum, E. Melamed, D. Offen, S. Melamed; Intravitreal Injections of Neurotrophic Factors Secreting Mesenchymal Stem Cells Are Neuroprotective in Post Optic Nerve-Transected Rat Eyes. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1673.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the neuroprotective effect of intravitreal injections of neurotrophic factors secreting mesenchymal stem cells on the survival of retinal ganglion cells (RGCs) in post optic nerve-transected rat eyes. The injected cells are bone marrow derived mesenchymal stem cells (MSC) that were induced into neurotrophic factors secreting cells (NTF-SC) to combine stem cell-based therapy with neurotrophic factors-based neuroprotection. NTF-SC produce and secret high levels of BDNF, GDNF, VEGF and IGF1.
A novel protocol was used to induce MSC of rat and human bone-marrow origin into neurotrophic factors secreting cells. The neuroprotective effect of intravitreal injections of either untreated MSC or NTF-SC was evaluated and compared to PBS injections using optic nerve transection model in rats (n = 132). A total of 400,000/5µl stem cells were injected into the vitreous. Systemic Cyclosporine was daily injected to some of the rats to assess the influence of immunosuppression. Retinal ganglion cells (RGCs) were labeled by applying Rhodamine Dextran to the orbital optic nerve or by injecting Fluorogold into the superior colliculus. Cells-treated and PBS-treated eyes were compared in a masked way 8 days after optic nerve transection. For cell tracking purposes, MSC were labeled with PKH26 and analyzed at 3 time points (time 0, 3 and 9 days) using immunohistochemistry and PCR.
Eight days after optic nerve transection, the mean RGCs damage was significantly reduced after intravitreal injections of NTF-SC of human origin (31% ± 3%, p = 0.0005) or un-treated MSC (34% ± 5%, p= 0.07) compared to PBS (54% ± 3%). When systemic immunosuppression was applied the mean RGCs damage was still significantly reduced after intravitreal injections of NTF-SC of human origin (55% ± 3% RGCs damage, compared to 62 ± 4% damage for un-treated MSC and 62 ± 3% for PBS injected eyes). Immunohistochemistry for transplanted NTF-SC demonstrated that stem cells survive in the retina and vitreous at least 9 days after injection. However, the number of cells was reduced on the 9th day compared to the day of injection.
Cell-based delivery of neurotrophic factors is significantly neuroprotective in optic nerve injury. This novel approach is a safe and efficacious method of generating NTFs in the eye and may be potentially neuroprotective in glaucoma. Similar experiments with glaucoma model are in progress.
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