Secretome derived from mesenchymal stromal cells primed with neurotrophic factors rescues Neuro-2a cells from endoplasmic reticulum stress-mediated loss of neurogenesis.

Abstract

Abstract Endoplasmic reticulum (ER) stress-mediated accumulation of misfolded protein is a plausible stimulus for the pathogenesis of neurodegenerative diseases (ND). Under physiological conditions, ER stress activates the unfolded protein response (UPR) that repairs the misfolded proteins. Hence, to develop a physiologically relevant in vitro model system, we exposed Neuro-2a cells to an ER stress inducer which significantly affected the neurite outgrowth parameters and expression of neuronal markers without causing cell death in them. Here, we demonstrate that ER stress triggers early apoptosis, inflammation, and stress kinase activation in Neuro-2a cells. We have previously reported the regenerative potential of mesenchymal stromal cells (MSCs)-derived secretome in reversing the oxidative stress-induced loss of neurogenesis. The aim of this study was to investigate whether priming of MSCs with neurotrophic factors would enhance their neuroprotective potential, for which we used two distinct approaches. In the first approach, the ER-stressed Neuro-2a cells were subjected to a single exposure of conditioned medium (CM) derived from both naïve (naïve CM) and primed MSCs (primed CM), while in the second approach, the ER-stressed cells were subjected to multiple exposures of both naïve and primed CM. We observed that exposure of ER stress-induced Neuro-2a cells to primed CM significantly restored the neurite outgrowth parameters along with the expression of neuronal markers and also suppressed the induction of early apoptosis, inflammation, and activation of stress kinases. These results clearly underscore the importance of priming the MSCs with neurotrophic factors for developing more effective therapeutic strategies to combat ND.