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Oliver W Gramlich, Alexander J Brown, Kyle Gonsalves, Randy H Kardon; Inhibition of Hif1 Signaling and Increased Lipid Metabolism are Associated with Retinal Ganglion Cell Protection in a Mouse Model of Multiple Sclerosis. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1395.
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© ARVO (1962-2015); The Authors (2016-present)
Acute optic neuritis is the initial symptom in 25-45% of newly diagnosed cases of Multiple Sclerosis (MS) leading to visual impairment. The purpose of our study is to uncover how systemic stem cell therapy recues the ocular phenotype in an experimental autoimmune encephalomyelitis (EAE) model.
EAE was induced in 36 female C57BL6 mice by immunization with MOG33-55, complete Freunds adjuvant and pertussis toxin. Half of the EAE mice received stem cells (EAE+SC) delivered intraperitoneally. Clinical progression was monitored according to a 5-point EAE scoring scheme. Retinal nerve fiber layer (RNFL) thickness and pattern electroretinogram (PERG) were measured 32 days after induction. Retinas were harvested, prepared for RNAseq and data was examined by Ingenuity pathway analysis. Statistical differences were calculated using ANOVA and post-Hoc tests.
EAE animals having received SC seven days after induction show significantly lower motor-sensory impairment (Area under the curve EAE: 43±1.5 vs. EAE+SC:30±1.4; P=0.0001), improvement in the PERG amplitude (EAE: 16.5±3.8µV vs. EAE+SC: 26.2±5.2ms; P=0.0002), and diminished RNFL thinning in the naso-temporal quadrant (EAE: 18±2.6µm vs. EAE+SC: 23±7.3µm; P=0.042). Nav3 (+35%; P=0.0008), Abca1(+49%; P=0.01) and Egln1 (-46%; P=0.0008) displayed the most dramatic changes in gene expression in the retina of EAE mice having received SC. Significantly increased expression of gene clusters related to neurogenesis, cholesterol recycling, Hif1 pathway repressors and lipid metabolism was evident in SC treated EAE mice when compared to untreated EAE animals. Down-regulated gene clusters in SC treated EAE mice were found for glycolysis and PPRgamma signaling.
Systemic SC treatment positively affects Retinal Ganglion Cell (RGC) survival in EAE. Besides regulation of Hif1-pathway in RGC, increased lipid metabolism and downregulated glycolysis might explain the functional improvement seen in PERG of EAE animals after SC treatment. Nav3 is important for neurogenesis and may facilitate RGC neuroprotection. In summary, we identified biochemical pathways which can be pharmacologically targeted to for the development of new treatment regimens for MS and RGC neuroprotection.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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