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Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats

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Abstract

Purpose

Ischemia-associated retinal degeneration is one of the leading causes of vision loss, and to date, there are no effective treatment options. We hypothesized that delayed injection of bone-marrow stem cells (BMSCs) 24 h after the onset of ischemia could effectively rescue ischemic retina from its consequences, including apoptosis, inflammation, and increased vascular permeability, thereby preventing retinal cell loss.

Methods

Retinal ischemia was induced in adult Wistar rats by increasing intraocular pressure (IOP) to 130–135 mmHg for 55 min. BMSCs harvested from rat femur were injected into the vitreous 24 h post-ischemia. Functional recovery was assessed 7 days later using electroretinography (ERG) measurements of the a-wave, b-wave, P2, scotopic threshold response (STR), and oscillatory potentials (OP). The retinal injury and anti-ischemic effects of BMSCs were quantitated by measuring apoptosis, autophagy, inflammatory markers, and retinal–blood barrier permeability. The distribution and fate of BMSC were qualitatively examined using real-time fundus imaging, and retinal flat mounts.

Results

Intravitreal delivery of BMSCs significantly improved recovery of the ERG a- and b-waves, OP, negative STR, and P2, and attenuated apoptosis as evidenced by decreased TUNEL and caspase-3 protein levels. BMSCs significantly increased autophagy, decreased inflammatory mediators (TNF-α, IL-1β, IL-6), and diminished retinal vascular permeability. BMSCs persisted in the vitreous and were also found within ischemic retina.

Conclusions

Taken together, our results indicate that intravitreal injection of BMSCs rescued the retina from ischemic damage in a rat model. The mechanisms include suppression of apoptosis, attenuation of inflammation and vascular permeability, and preservation of autophagy.

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Authors and Affiliations

  1. Department of Anesthesiology, University of Illinois Medical Center, 1740 West Taylor Street, MC 515, Chicago, IL, 60612, USA

    Biji Mathew, Leianne Torres, Jasmine Lopez & Steven Roth

  2. Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA

    Jacqueline N. Poston & John C. Dreixler

  3. Department of Ophthalmology, University of Illinois at Chicago, Chicago, IL, USA

    Ruth Zelkha & Steven Roth

  4. Department of Neurosurgery, Northwestern University, Chicago, IL, USA

    Irina Balyasnikova & Maciej S. Lesniak

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  1. Biji Mathew
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Corresponding author

Correspondence to Steven Roth.

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Funding

This study was supported by National Institutes of Health (Rockville, MD, USA) grants EY10343 and EY10343-16S1 (American Recovery and Reinvestment Act) to Dr. Roth, NS087990 to Dr. Lesniak and to Dr. Balyasnikova, AG029795 for the Medical Student Summer Research Program at the University of Chicago Pritzker School of Medicine, UL1RR024999 to the University of Chicago Institute for Translational Medicine; the Illinois Society for the Prevention of Blindness, Chicago (Dr. Poston); Core Grant P30 EY001792 (to the Department of Ophthalmology, University of Illinois at Chicago, Chicago); and a Center-Style Grant from the Dean’s Research Advisory Committee of the Division of Biological Sciences of the University of Chicago (Drs. Lesniak and Roth). Jacqueline N. Poston was the recipient of a Medical Student Research Fellowship Award from the American Academy of Neurology (St. Paul, MN, USA) and a student scholarship from the Achievement Rewards for College Scientists Foundation (Washington, DC, USA). There was no involvement of the funding bodies in the design of the study or in collection, analysis, and interpretation of the data or the writing of the manuscript.

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval: Animal experiments

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care Committees of the Universities of Chicago and Illinois.

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Mathew, B., Poston, J.N., Dreixler, J.C. et al. Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats. Graefes Arch Clin Exp Ophthalmol 255, 1581–1592 (2017). https://doi.org/10.1007/s00417-017-3690-1

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