Intravitreal Co-Administration of GDNF and CNTF Confers Synergistic and Long-Lasting Protection against Injury-Induced Cell Death of Retinal Ganglion Cells in Mice

Simon Dulz,Mahmoud Bassal,Udo Bartsch,Stefanie Schlichting,Susanne Bartsch,Kai Flachsbarth,Boris Fehse,Kristoffer Riecken

doi:10.3390/cells9092082

Abstract

We have recently demonstrated that neural stem cell-based intravitreal co-administration of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) confers profound protection to injured retinal ganglion cells (RGCs) in a mouse optic nerve crush model, resulting in the survival of ~38% RGCs two months after the nerve lesion. Here, we analyzed whether this neuroprotective effect is long-lasting and studied the impact of the pronounced RGC rescue on axonal regeneration. To this aim, we co-injected a GDNF- and a CNTF-overexpressing neural stem cell line into the vitreous cavity of adult mice one day after an optic nerve crush and determined the number of surviving RGCs 4, 6 and 8 months after the lesion. Remarkably, we found no significant decrease in the number of surviving RGCs between the successive analysis time points, indicating that the combined administration of GDNF and CNTF conferred lifelong protection to injured RGCs. While the simultaneous administration of GDNF and CNTF stimulated pronounced intraretinal axon growth when compared to retinas treated with either factor alone, numbers of regenerating axons in the distal optic nerve stumps were similar in animals co-treated with both factors and animals treated with CNTF only.

Highlights

Retinal ganglion cells (RGCs) comprise a heterogeneous group of projection neurons which integrate and transmit visual information from the retina to the brain
We have recently demonstrated that sustained neural stem cell-based intravitreal co-administration of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) confers profound synergistic neuroprotection to injured RGCs in a mouse optic nerve crush model [36]
Neural stem (NS) cells were transduced by spinoculation with either a bicistronic lentiviral vector encoding GDNF, together with the reporter protein enhanced green fluorescent protein fused to a neomycin resistance, or a bicistronic vector encoding a secretable variant of CNTF, together with the reporter protein Venus linked to zeocin resistance by a 2A peptide (Figure 1)

Summary

Introduction

Retinal ganglion cells (RGCs) comprise a heterogeneous group of projection neurons which integrate and transmit visual information from the retina to the brain. Which project to more than 40 different targets in the brain [4]. RGCs display striking heterogeneity in their susceptibility to pathological conditions and their ability to regrow injured axons over long distances in response to regeneration-promoting treatments [5,6,7]. Loss of RGCs, as occurs in traumatic, inflammatory, ischemic, hereditary or glaucomatous optic neuropathies, results in visual deterioration and is a leading cause of irreversible blindness [8,9]. Elevated intraocular pressure (IOP) is the most important risk factor for glaucoma, the most prevalent optic neuropathy

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Conclusion