Protective Effect of Intravitreal Administration of Exosomes Derived from Mesenchymal Stem Cells on Retinal Ischemia

ABSTRACT

Purpose: Exosomes derived from human mesenchymal stem cells (hMSCs) cultured under hypoxic conditions contain proteins and growth factors that promote angiogenesis. This study investigated the effect of intravitreal administration of these exosomes on retinal ischemia using a murine model.

Methods: Oxygen-induced retinopathy (OIR) was induced by exposing one-week-old male C57BL/6J mice to 5 days of 75% hyperoxic conditioning, and returning to room air. After hyperoxic conditioning, the right eye of each mouse was injected intravitreally with 1 µl saline or exosomes derived from hMSCs and compared to control mice of the same age raised in room air without OIR injected intravitreally with saline. Two weeks post-injection, fluorescein angiography (FA) and phase-variance optical coherence tomography angiography (pvOCTA) were used to assess retinal perfusion. Retinal thickness was determined by OCT. The extent of retinal neovascularization was quantitated histologically by counting vascular nuclei on the retinal surface.

Results: Among eyes with OIR, intravitreal exosome treatment partially preserved retinal vascular flow in vivo and reduced associated retinal thinning; retinal thickness on OCT was 111.1 ± 7.4µm with saline versus 132.1 ± 11.6µm with exosome, p < 0.001. Retinal neovascularization among OIR eyes was reduced with exosome treatment when compared to saline-treated eyes (7.75 ± 3.68 versus 2.68 ± 1.35 neovascular nuclei per section, p < 0.0001). No immunogenicity or ocular/systemic adverse effect was associated with intravitreal exosome treatment.

Conclusions: Intravitreal administration of exosomes derived from hMSCs was well tolerated without immunosuppression and decreased the severity of retinal ischemia in this murine model. This appealing novel non-cellular therapeutic approach warrants further exploration.

KEYWORDS:

• Angiogenesis
• exosomes
• mesenchymal stem cells
• oxygen induced retinopathy
• retinal ischemia

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper..

Funding

This study was supported in part by the University of California, Davis Eye Center Retina Research Fund. JAN is supported by the California Institute for Regenerative Medicine and an NIH Common fund transformative research projects grant 1R01GM099688. JDA is supported by NSF GRFP 2011116000, NIH T32-GM008799, NSF GROW 201111600, and NIH T32-HL086350. The in vivo retinal imaging of mice was conducted at the UC Davis RISE Eye-Pod laboratory supported by the UC Davis Research Investments in Science and Engineering (RISE) initiative, UC Davis NEI Vision Core Grant EY 012576 and NSF I/UCRC CBSS Grant. This work was presented in part as a paper presentation at the Retina Society meeting as recipient of the Retina Society Fellow Research Award (EM), September 15, 2016, San Diego, CA.

Additional information

Funding

This study was supported in part by the University of California, Davis Eye Center Retina Research Fund. JAN is supported by the California Institute for Regenerative Medicine and an NIH Common fund transformative research projects grant 1R01GM099688. JDA is supported by NSF GRFP 2011116000, NIH T32-GM008799, NSF GROW 201111600, and NIH T32-HL086350. The in vivo retinal imaging of mice was conducted at the UC Davis RISE Eye-Pod laboratory supported by the UC Davis Research Investments in Science and Engineering (RISE) initiative, UC Davis NEI Vision Core Grant EY 012576 and NSF I/UCRC CBSS Grant. This work was presented in part as a paper presentation at the Retina Society meeting as recipient of the Retina Society Fellow Research Award (EM), September 15, 2016, San Diego, CA.