Congruent to our studying of the pathophysiology of glaucoma, our focus is also on the development of potential treatments. Retinal ganglion cell (RGC) loss is a hallmark of glaucoma and optic neuropathies. Previously we demonstrated that intravitreal injection of small extracellular vesicles (sEV), produced by human bone marrow-derived mesenchymal stem cells (BMSC), but not human dermal fibroblasts, provided statistically significant RGC neuroprotection and regeneration of their axons, while partially preventing RGC dysfunction and axonal loss in rat models of optic nerve crush (ONC) and glaucoma (laser or microbead), as well in a long term (one year) mouse genetic DBA/2J model of glaucoma. Our data suggest that sEV-derived miRNAs play an important role in RGC neuroprotection, and several candidate miRNAs participating in neuroprotection have been identified and tested. Adeno-associated virus (AAV2) expressing a combination of three different candidate miRNAs were intravitreally injected into rat eyes one week before ONC injury. Delivery of selected combinations of miRNAs before ONC provided significant RGC neuroprotection. However, no single miRNA appeared to be responsible for the effects observed, whilst positive effects observed appeared to coincide with successful knockdown of PTEN expression in the retina. We concluded that viral delivery of miRNAs provides a possible neuroprotective strategy for injured RGCs and is conducive to therapeutic manipulation. Further investigation into miRNA candidates is required however. To better understand the changes that BMSC-derived exosomes/sEV undergo when exposed to the injured retinal environment and whether their therapeutic efficacy can be increased, we primed BMSC by pre-treatment with dissociated retinal cell culture conditioned medium or TNF. We hypothesized that emulating an inflammatory environment would make the BMSC enter a more therapeutically active state and release more neuroprotective compounds, including exosomes/sEV. We demonstrated that priming of BMSC with retinal conditioned medium or TNF significantly increased neuroprotective effect of BMSC-derived sEV on injured rat and human RGCs. Since our data suggest that miRNAs play an important role in RGC neuroprotection, we analyzed changes in rat RGC miRNA composition after ONC (2 or 7 days) or after intraocular pressure elevation. The levels of several miRNAs were dramatically changed after insults. Some miRNAs showed similar changes between ONC and intraocular pressure elevation groups, while some miRNAs changes were specific to the modality of insult. Finally, many changes were not apparent till 7 days post-injury and further investigation is required to determine the role miRNA play in the neurodegenerative response of the retina. Previous studies have demonstrated that brorin promotes neurogenesis. Using the same ONC model as above, intravitreal injection of recombinant AAV2 was performed to express brorin in RGCs. Overexpression of brorin by intravitreal injection two weeks prior to optic nerve crush promoted RGC survival, as assessed by immunohistochemistry/RGC counting.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Mead, Ben; Amaral, Juan; Tomarev, Stanislav (2018) Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma. Invest Ophthalmol Vis Sci 59:702-714
Mead, Ben; Tomarev, Stanislav (2018) Retinal ganglion cell neuroprotection by growth factors and exosomes: lessons from mesenchymal stem cells. Neural Regen Res 13:228-229
Joe, Myung Kuk; Lieberman, Raquel L; Nakaya, Naoki et al. (2017) Myocilin Regulates Metalloprotease 2 Activity Through Interaction With TIMP3. Invest Ophthalmol Vis Sci 58:5308-5318
Takahama, Shokichi; Adetunji, Modupe O; Zhao, Tantai et al. (2017) Retinal Astrocytes and GABAergic Wide-Field Amacrine Cells Express PDGFR?: Connection to Retinal Ganglion Cell Neuroprotection by PDGF-AA. Invest Ophthalmol Vis Sci 58:4703-4711
Mead, Ben; Tomarev, Stanislav (2017) Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. Stem Cells Transl Med 6:1273-1285
Mead, Ben; Tomarev, Stanislav (2016) Evaluating retinal ganglion cell loss and dysfunction. Exp Eye Res 151:96-106
Morgan, Joshua T; Kwon, Heung Sun; Wood, Joshua A et al. (2015) Thermally labile components of aqueous humor potently induce osteogenic potential in adipose-derived mesenchymal stem cells. Exp Eye Res 135:127-33
Joe, Myung Kuk; Nakaya, Naoki; Abu-Asab, Mones et al. (2015) Mutated myocilin and heterozygous Sod2 deficiency act synergistically in a mouse model of open-angle glaucoma. Hum Mol Genet 24:3322-34
Johnson, Thomas V; DeKorver, Nicholas W; Levasseur, Victoria A et al. (2014) Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain 137:503-19
Kwon, Heung Sun; Nakaya, Naoki; Abu-Asab, Mones et al. (2014) Myocilin is involved in NgR1/Lingo-1-mediated oligodendrocyte differentiation and myelination of the optic nerve. J Neurosci 34:5539-51

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