TNFα-Mediated Priming of Mesenchymal Stem Cells Enhances Their Neuroprotective Effect on Retinal Ganglion Cells

PURPOSE. To determine whether priming of bone marrow mesenchymal stem cells (MSCs) by signals from injured retina, particularly tumor necrosis factor a (TNF alpha), increase their exosomes' neuroprotective efficacy on retinal ganglion cells (RGCs). METHODS. MSCs were primed with retinal cell culture conditioned medium, with or without the TNF alpha blocker etanercept or TNF alpha prior to isolation of exosomes. MSC conditioned medium or exosomes were added to rat retinal cultures or human stem cell derived retinal ganglion cell (hRGC) cultures, and RGC neuroprotective effects were quantified. Luminex assays were used to compare primed versus unprimed exosomes. RESULTS. MSC conditioned medium and exosomes exerted a significant neuroprotective effect on injured rat and hRGC. This effect was significantly increased after MSCs were primed with retinal conditioned medium or TNF alpha. Blocking of TNF alpha signaling with etanercept prevented priming-induced RGC neuroprotective efficacy. Priming increased Pigment epithelium-derived factor (PEDF) and VEGF-AA exosomal abundance. CONCLUSIONS. MSC exosomes promote RGC survival not just in rodent retinal cultures but also with hRGC. Their efficacy can be further enhanced through TNF alpha priming with the mechanism of action potentially mediated, at least in part, through increased levels of PEDF and VEGF-AA.