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Ben Mead, Juan Amaral, Zubair Ahmed, Stanislav I Tomarev; BMSC-derived exosomes promote retinal ganglion cell survival in multiple rodent models of glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2615. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously demonstrated that exosomes derived from human bone marrow mesenchymal stem cells (BMSC) provide retinal ganglion cell (RGC) neuroprotection in a rat optic nerve crush model (ARVO 2017, Abstract Vol.58, 2953). The present study aimed to test neuroprotective effects of human-derived BMSC exosomes in three different rodent glaucoma models.
Exosomes were isolated from human BMSC and fibroblasts and characterized by NanoSight and Western blot. To experimentally induce glaucoma, we used DBA/2J mice or rats receiving either an intracameral injection of microbeads or a laser photocoagulation of the trabecular meshwork and circumferential limbal vessels. Exosomes were intravitreally injected at a concentration of 3x109, weekly (rat models) or monthly (microbead rat model and DBA/2J mice). Intraocular pressure (IOP), positive scotopic threshold response (pSTR) and retinal nerve fibre layer (RNFL) recordings were taken. RBPMS+ RGC were counted in retinal wholemounts and paraphenylenediamine+ (PPD) axons were counted in optic nerve sections. RNAseq was used to quantify miRNA present in human-derived BMSC and fibroblast exosomes, and mRNA in rat-derived RGC, with or without BMSC-exosome treatment.
All three glaucoma models exhibited elevated IOP, RGC dysfunction and loss, and axonal degeneration. In both laser and microbead rat models, BMSC but not fibroblast exosomes promoted significant preservation of RGC function, as measured by pSTR amplitudes, and significant neuroprotection of RBPMS+ RGC as quantified in retinal wholemounts. BMSC but not fibroblast exosomes prevented axonal degeneration as evaluated by RNFL thickness and PPD+ axonal scaling. Knockdown of the AGO2 gene encoding a protein critical for miRNA function and packing into exosomes prior to exosome isolation significantly attenuated the above effects indicating that miRNA play an important role in RGC neuroprotection. RNAseq detected 43 miRNA abundant in BMSC exosomes in comparison to fibroblast exosomes. Long-term neuroprotective effects (one year) of monthly BMSC exosome injections are currently being tested in the DBA/2J model.
We demonstrate for the first time that BMSC-derived exosomes offer significant therapeutic benefit in rodent models of glaucoma and provide a possible mechanism by which BMSC exosomes deliver miRNA to downregulate key mRNA and elicit RGC neuroprotection.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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