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

Oliver W Gramlich; Alexander J Brown; Cheyanne R Godwin; Michael S Chimenti; Lauren K Boland; James A Ankrum; Randy H Kardon

doi:10.1167/tvst.9.8.16

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

Transl Vis Sci Technol. 2020 Jul 10;9(8):16. doi: 10.1167/tvst.9.8.16. eCollection 2020 Jul.

Authors

Oliver W Gramlich^{1

2}, Alexander J Brown^{3

4}, Cheyanne R Godwin^{1

2}, Michael S Chimenti⁵, Lauren K Boland⁶, James A Ankrum⁶, Randy H Kardon^{1

2}

Affiliations

¹ Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA.
² Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System, Iowa City, IA, USA.
³ Department of Biomedical Research, National Jewish Health, Denver, CO, USA.
⁴ Department of Immunology & Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁵ Iowa Institute of Human Genetics, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.
⁶ Roy J. Carver Department of Biomedical Engineering College, The University of Iowa, Iowa City, IA, USA.

Abstract

Purpose: 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 RNA-sequencing.

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.

Keywords: EAE; mesenchymal stem cells; optic neuritis; pattern-ERG; retinal ganglion cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Female
Mesenchymal Stem Cells*
Mice
Mice, Inbred C57BL
Multiple Sclerosis* / therapy
Myelin-Oligodendrocyte Glycoprotein
Retinal Ganglion Cells

Substances

Myelin-Oligodendrocyte Glycoprotein

Abstract

Publication types

MeSH terms

Substances

Grants and funding