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

Abstract

Citation: Mead B, Chamling X, Zack DJ, Ahmed Z, Tomarev S. TNFα-mediated priming of mesenchymal stem cells enhances their neuroprotective effect on retinal ganglion cells. Invest Ophthalmol Vis Sci. 2020;61(2):6. https://doi.org/10.1167/iovs.61.2.6 PURPOSE.To determine whether priming of bone marrow mesenchymal stem cells (MSCs) by signals from injured retina, particularly tumor necrosis factor α (TNFα), increase their exosomes' neuroprotective efficacy on retinal ganglion cells (RGCs). METHODS.MSCs were primed with retinal cell culture conditioned medium, with or without the TNFα blocker etanercept or TNFα 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 TNFα. Blocking of TNFα 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 TNFα priming with the mechanism of action potentially mediated, at least in part, through increased levels of PEDF and VEGF-AA.

Modulation of p75NTR on Mesenchymal Stem Cells Increases Their Vascular Protection in Retinal Ischemia-Reperfusion Mouse Model

“…In support of our observation, a prior study reported that MSCs-secreted VEGF mediates the differentiation of endothelial progenitor cells into endothelial cells via paracrine mechanisms [ 47 ]. MSCs-secreted VEGF was also shown to play a part in underlying paracrine and neuroprotective action of MSCs [ 48 ]. NGF is another potential trophic factor that can contribute to enhanced reparative potential of p75 NTR -silenced MSCs.…”

Human Wharton’s Jelly Mesenchymal Stem Cells Protect Neural Cells from Oxidative Stress Through Paracrine Mechanisms

“…These results show that the presence of WJ-MSCs after the insult is crucial for the improvement of hippocampal cell survival. Importantly, many studies that have assessed the paracrine effects of MSCs have transferred the conditioned medium from MSCs to other cell cultures [ 39 , 40 ]. In the present study, we used a coculture system that allowed the bi-directional interaction between WJ-MSCs and neural cells, without physical contact between the two cell types.…”

Challenges and advances in clinical applications of mesenchymal stromal cells

“…Priming has also been referred to as licensing or preconditioning, which is a concept commonly used in the field of immunology, and it has been adapted to the scope of stem cells [ 144 , 145 ]. One of the commonly used strategies is priming MSCs with pro-inflammatory mediators, including IFN-γ, TNF-α, IL-1α, and IL-1β, and more priming approaches are being proposed to improve the function, survival, and therapeutic efficacy of MSCs [ 146 , 147 ]. The priming approaches could be divided into three categories based on the stimulations: (a) MSCs priming with small molecules, (b) MSCs priming with hypoxia, (c) MSCs priming with biomaterials.…”