Systemic Mesenchymal Stem Cell Treatment Mitigates Structural and Functional Retinal Ganglion Cell Degeneration in a Mouse Model of Multiple Sclerosis

Abstract

The purpose of this study was to determine mesenchymal stem cell (MSC) therapy efficacy on rescuing the visual system in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) and to provide new mechanistic insights. Methods: EAE was induced in female C57BL6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 , complete Freund's adjuvant, and pertussis toxin. The findings were compared to sham-immunized mice. Half of the EAE mice received intraperitoneally delivered stem cells (EAE + MSC). Clinical progression was monitored according to a five-point EAE scoring scheme. Pattern electroretinogram (PERG) and retinal nerve fiber layer (RNFL) thickness were measured 32 days after induction. Retinas were harvested to determine retinal ganglion cell (RGC) density and prepared for RNAsequencing. Results: EAE animals that received MSC treatment seven days after EAE induction showed significantly lower motor-sensory impairment, improvement in the PERG amplitude, and preserved RNFL. Analysis of RNA-sequencing data demonstrated statistically significant differences in gene expression in the retina of MSC-treated EAE mice. Differentially expressed genes were enriched for pathways involved in endoplasmic reticulum stress, endothelial cell differentiation, HIF-1 signaling, and cholesterol transport in the MSC-treated EAE group. Conclusions: Systemic MSC treatment positively affects RGC function and survival in EAE mice. Better cholesterol handling by increased expression of Abca1, the cholesterol efflux regulatory protein, paired with the resolution of HIF-1 signaling activation might explain the improvements seen in PERG of EAE animals after MSC treatment. Translational Relevance: Using MSC therapy in a mouse model of MS, we discovered previously unappreciated biochemical pathways associated with RGC neuroprotection, which have the potential to be pharmacologically targeted as a new treatment regimen.

Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases

“…Optic neuritis is an inflammatory demyelinating disorder of the optic nerve, often related to multiple sclerosis (Redler and Levy, 2020 ). Intraperitoneal injection of human BM-MSCs decreased RGC death and improved their function in a mouse model of multiple sclerosis (Gramlich et al, 2020 ). BM-MSCs administered intravenously proved to be safe for patients with neuromyelitis spectrum disorder and improved neurological disability, with recovery in neural structures in the optic nerve and retina for up 2 years after treatment (Fu et al, 2016 ).…”

Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

“…Finally-and since some of the current CTs are directed at the involvement of the optic nerve in multiple sclerosis-it is worth reviewing an experimental approach that may be interesting. Recently, Gramlich et al [117] aimed to determine the efficacy of MSC therapy on rescuing the visual system in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Systemic MSC treatment (intraperitoneally) was found to positively affect RGC function and survival in EAE mice.…”

Emerging concepts in the treatment of optic neuritis: mesenchymal stem cell-derived extracellular vesicles

“…There was significantly lower motor-sensory impairment, improved pattern electroretinogram, and preserved retinal nerve fiber layer. Increased expression of Abca1, a cholesterol efflux regulatory protein, and reduced HIF-1 were present, although the functional roles of these gene expression alterations were not examined, leaving the mechanism of improvement still uncertain [ 65 ].…”