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Mesenchymal stem cell-derived small extracellular vesicles promote Neuroprotection in Rodent Models of Glaucoma

Mead, Ben, Amaral, Juan and Tomarev, Stanislav 2018. Mesenchymal stem cell-derived small extracellular vesicles promote Neuroprotection in Rodent Models of Glaucoma. Investigative Ophthalmology & Visual Science 59 (2) , pp. 702-714. 10.1167/iovs.17-22855

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Abstract

Purpose: To investigate the benefit of bone marrow mesenchymal stem cell (BMSC)-derived small extracellular vesicles (sEV) as an intravitreal (ivit) therapy in two rat models of glaucoma and to determine and identify candidate miRNA involved in the mechanism. Methods: sEV were isolated from human BMSC and fibroblasts and ivit injected into adult rats after induction of elevated IOP. IOP was elevated using either intracameral injection of microbeads or laser photocoagulation of circumferential limbal vessels and the trabecular meshwork. Retinal nerve fiber layer (RNFL) thickness was measured using optical coherence tomography, positive scotopic threshold response (pSTR) recorded using ERG, and RNA binding protein with multiple splicing (RBPMS+) retinal ganglion cell (RGC) counted using retinal wholemounts. sEV miRNA were sequenced using RNAseq. Results: sEV isolated from BMSC promoted significant neuroprotection of RGC while preventing RNFL degenerative thinning and loss of pSTR. sEV proved therapeutically efficacious when ivit injected every week or every month, but ineffective with longer delays between treatments. Knockdown of Argonaute2 (AGO2), a protein critical for miRNA function and packing into sEV prior to sEV isolation, significantly attenuated the above effects. Addition of BMSC sEV (but not fibroblast sEV) reduced death of cultured purified RGC. RNAseq identified 43 miRNA upregulated in BMSC sEV in comparison to fibroblast sEV, which yielded no neuroprotective effects. Conclusions: Injection of BMSC-derived sEV into the vitreous provided significant therapeutic benefit to glaucomatous eyes. The neuroprotective effect of sEV, at least partially, may be explained by direct action on RGC through miRNA-dependent mechanisms.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Optometry and Vision Sciences
Publisher: Association for Research in Vision and Ophthalmology
ISSN: 0146-0404
Date of First Compliant Deposit: 12 November 2019
Date of Acceptance: 4 January 2018
Last Modified: 17 Apr 2020 08:15
URI: http://orca.cf.ac.uk/id/eprint/126600

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