Activated Omental Stromal Cells Protect Against Light-Induced Retinal Injury

24 th Annual Loyola Ophthalmology Resident-Alumni/Mission Day Evan Price, M.D., Ping Bu, M.D., Periannan Sethupathi, Ph.D., Evan Stubbs, Ph.D., Jay Perlman, M.D., Ph.D.

June 14, 2013

The authors have no financial disclosures to report

Objectives

• To review the state of stem cell research as it pertains to ophthalmic disease • To understand the findings of the current study • To discuss the implications of the research performed and possible future areas of study

Background

• Retinal diseases comprise a large share of the visual morbidity in the world (1-3) • There is a great need for treatments of retinal disease that will restore vision that has already been lost • E.g., nonexudative macular degeneration (4)

Background

• Stem cell therapies may provide the solutions these patients have been waiting for (5-7) – – – – Limbal stem cell deficiency Glaucoma Retinal vascular disease Degenerative retinal disease • Sources of stem cells for retinal applications – Embryonic stem cells (ESCs) – – – Induced pluripotent stem cells (iPSCs) Endothelial progenitor cells (EPCs) from umbilical cord blood or bone marrow Omental stromal cells (OSCs)

Background

• The regenerative and immunosuppressive properties of activated omentum are an area of active research (8-11) – – – – – Spinal cord Pancreas Kidney Skin Lungs

Our Research

• Experimental animal study looking at the effect of activated OSCs on light-damaged mouse retinas – Morphology – Function (ERG) • Male BALB/c albino mice were divided into 2 groups (n=4 for each group) – OSC-treated group – Vehicle-treated group (control)

Electroretinography

• Performed prior to and six days after light exposure – Dark adapted overnight – – Wire loop electrode in contact with the cornea (12) Single-flash stimulus • Light injury (13) – – – 12 hours dark adaptation Eyes dilated 6000 lux of white light for 4 hours Photo by Evan Price

Methods

• Isolation of OSCs from activated mouse omentum – Male BALB/c albino mice – – – Intraperitoneal injection of a polydextran particle slurry Omenta harvested Collagenase I digestion • Intraperitoneal injection • Outcomes – Six days after light exposure – – ERGs performed Retinas examined histologically

Results

Results

Results/Conclusions

Vehicle Pre: 445.7 ± 27.9 μV Post: 74.2 ± 9.3 μV OSC Pre: 477.6 ± 6.6 μV Post: 127.2 ± 16.4 μV Vehicle Pre: 980.4 ± 54.5 μV Post: 164.8 ± 37.3 μV OSC Pre: 1023.1 ± 62.6 μV Post: 323.2 ± 44.6 μV

Limitations/Future Directions

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Sample size

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Amount of light exposure

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Route of injection

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References

1. Congdon N, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477–485.

2. Resnikoff S, et al. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82(11):844–851.

3. Friedman DS, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564–572.

4. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. Arch Ophthalmol. 2001;119:1417-1436.

5. Marchetti V, Krohne TU, Friedlander DF, Friedlander M. Stemming vision loss with stem cells. J Clin Invest. 2010;120(9):3012–3021.

6. Idelson M, et al. Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells. Cell Stem Cell. 2009;5(4):396–408.

7. Carr AJ, et al. Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS One. 2009;4(12):e8152.

8. Singh AK, Patel J, Litbarg NO, Gudehithlu KP, Sethupathi P, et al. Stromal cells cultured from omentum express pluripotent markers, produce high amounts of VEGF, and engraft to injured sites. Cell Tissue Res. 2008;332:81-8.

9. Singh AK, Gudehithlu KP, Litbarg NO, Sethupathi P, Arruda JA, Dunea G. Transplanting fragments of diabetic pancreas into activated omentum gives rise to new insulin producing cells. Biochem Biophys Res Commun. 2007;355(1):258-62.

10. Braun R, et al. Omental Stromal Cells (OSC) reduce Acute Lung Injury After Allogenic Transplantation Without Immunosuppression. Am J Respir Crit Care Med. 2010;181:A1085.

11. Goldsmith HS. The evolution of omentum transposition: from lymphedema to spinal cord, stroke and Alzheimer’s disease. Neurol Res. 2004;26:586–593.

12. Bu P, Basith B, Stubbs EB, Jr., Perlman JI. 2010. Granulocyte colony-stimulating factor facilitates recovery of retinal function following retinal ischemic injury. Exp Eye Res 91:104-6.

13. Oishi A, Otani A, Sasahara M, Kojima H, Nakamura H, et al. Granulocyte colony-stimulating factor protects retinal photoreceptor cells against light-induced damage. Invest Ophthalmol Vis Sci. 2008;49:5629-35.