Abstract:

Retinal ganglions cells (RGCs) are responsible for propagating electrochemical information from the eye to the brain along their axons which make up the optic nerve. The loss of RGCs is characteristic in several conditions such as glaucoma and traumatic optic neuropathy and leads to visual loss and blindness.While no therapy exists to directly treat RGCs, the use of bone marrow-derived mesenchymal stem cells (BMSCs) has shown promise in eliciting significant RGC neuroprotection. Their efficacy is proven in both in vitro (retinal co-culture (Mead et al.,2014) and organotypic retinal explants (Johnson et al., 2014))and in vivo (ocular hypertension (Johnson et al., 2010) and optic nerve crush (Mesentier-Louro et al., 2014)) models from multiple laboratories and are currently being investigated in clinical trials (reviewed in Mead et al., 2015). While other MSCs exist,such as those isolated from adipose tissue, umbilical cord blood and dental pulp, and have even been demonstrated to act differently in neuroprotective assays (Mead et al., 2014), BMSCs are the most widely studied and the predominant MSC undergoing clinical trials. Although BMSCs do not replace retinal cells and their mechanism of action is exclusively through the secretion of neuroprotective compounds, BMSCs represent an exciting candidate for cellular therapy of the retina. A large body of evidence exists for the efficacious use of BMSCs in several eye disease models and over ten stage 1 clinical trials are underway (Reviewed in Mead et al., 2015). While many of these trials have now reported good findings with successful transplantation into patients, the safety aspect of delivering living, dividing cells into the eye can still be questioned given the recent case study of three patients going blind after receiving intravitreal adipose-derived MSCs (Kuriyan et al., 2017). Issues such as hemorrhage and retinal detachment were observed and may reflect a possible side effect of intravitreal cell therapy. What is also not clear is the “shelf-life” of the BMSCs, particularly considering that they will need to be stored in liquid nitrogen, or grown and maintained at 37°C/5% CO2. These requirements add further costs and expertise needed for such a treatment while also introducing variability,particularly since the longer the cells are grown the lower the titers of secreted neuroprotective compounds (Mead et al., 2014).Another issue is that the BMSCs secretome contains a wide variety of compounds, some of which, such as vascular endothelial growth factor (VEGF), may be detrimental to the retina in high concentrations. While using BMSCs as a therapy is one avenue of research, understanding of their mechanism and the development of new treatments, independent of the cells themselves is equally important and would circumnavigate much of the issues detailed above. Our research has identified two very different modalities by which BMSCs protect RGCs, secretion of multiple neuroprotective peptides, of which platelet-derived growth factor (PDGF)-AA was the most neuroprotective, and secretion of extracellular vesicles including exosomes.