April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Elucidating Mechanisms of Retinal Ganglion Cell Neuroprotection by Mesenchymal Stem Cell Transplantation
Author Affiliations & Notes
  • Nicholas W. DeKorver
    Molecular Mechanisms of Glaucoma Section, National Eye Institute, National Institutes of Health, Rockville, Maryland
  • Thomas V. Johnson
    Molecular Mechanisms of Glaucoma Section, National Eye Institute, National Institutes of Health, Rockville, Maryland
    Centre for Brain Repair, Dept of Ophthalmology, University of Cambridge, Cambridge, United Kingdom
  • Natalie D. Bull
    Centre for Brain Repair, Dept of Ophthalmology, University of Cambridge, Cambridge, United Kingdom
  • Keith R. Martin
    Centre for Brain Repair, Dept of Ophthalmology, University of Cambridge, Cambridge, United Kingdom
  • Stanislav I. Tomarev
    Molecular Mechanisms of Glaucoma Section, National Eye Institute, National Institutes of Health, Rockville, Maryland
  • Footnotes
    Commercial Relationships  Nicholas W. DeKorver, None; Thomas V. Johnson, None; Natalie D. Bull, None; Keith R. Martin, None; Stanislav I. Tomarev, None
  • Footnotes
    Support  NEI Intramural Research Program; Prevention of Blindness Society of Metropolitan Washington
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 2603. doi:
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      Nicholas W. DeKorver, Thomas V. Johnson, Natalie D. Bull, Keith R. Martin, Stanislav I. Tomarev; Elucidating Mechanisms of Retinal Ganglion Cell Neuroprotection by Mesenchymal Stem Cell Transplantation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2603.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Previously we reported that mesenchymal stem cells (MSCs) co-cultured with retinal explants protect against retinal ganglion cell (RGC) death. Here we investigate the mechanisms of this neuroprotection.

Methods: : MSCs or fibroblasts were transplanted onto adult rat organotypic retinal explants and co-cultured for 7 days. Serum-free media was conditioned by 3 day cell culture incubation and concentrated roughly 40-fold. Retinal explants were treated twice daily with concentrated conditioned media (CCM). RGC survival was assessed as linear density of Islet-1+ and NeuN+ cells in the RGC layer. Concentrations of various factors in CCM were measured using multiplexed xMAP assays and ELISA.

Results: : Human MSC (hMSC) transplantation increased RGC survival (p<0.01 for all comparisons) compared to saline control (39.2±1.7 vs 21.4±0.8 Islet-1+ cells/mm; 42.0±2.1 vs 33.3±0.9 NeuN+ cells/mm) or human fibroblast transplantation (26.2±0.9 and 31.6±1.7 cells/mm, respectively). Similar effects were observed comparing rat MSCs to saline or murine fibroblasts. Treatment with rat MSC CCM increased RGC survival compared to controls (21.9±0.3 vs 13.8±0.6 Islet-1+ cells/mm; 79.6±1.9 vs 66.9±3.1 NeuN+ cells/mm; p<0.01 for both comparisons). Application of hMSC CCM did not improve RGC survival compared to saline, however treatment with fibroblast CCM significantly (p<0.05) reduced RGC survival (33.7±4.1 vs 44.8± 2.3 or 41.2±1.5 NeuN+ cells/mm) compared to hMSC CCM or saline, respectively. Among 27 factors analyzed, hMSCs secreted IL-2, IL-6, IL-13, IFN-γ, LIF, BDNF, NGF, PDGF-AA, TSP-1, and melatonin at levels 5-500 fold higher than fibroblasts. In contrast, human fibroblasts secreted EGF and bFGF at ≥50 fold higher levels than hMSCs.

Conclusions: : Transplantation of MSCs evokes robust RGC neuroprotection that may be mediated by secreted factors. Reduced efficacy of hMSC CCM could be due to inadequate concentrations of survival promoting factors relative to inhibitors, or could suggest that cellular contact is important for neuroprotection. Continuing work aims to improve treatment protocols to maximize RGC neuroprotection and to determine the effects of MSC-specific secreted factors on RGCs.

Keywords: neuroprotection • ganglion cells • cell survival 
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