MicroRNA-21a-5p/PDCD4 axis Regulates Mesenchymal-Stem-Cell-Induced Neuroprotection in Acute Glaucoma

Abstract

Abstract The clinical application of mesenchymal stem cells (MSCs) yields promising therapeutic benefits for a variety of neurological diseases, but underlying mechanisms are poorly understood. Here we show that intravitreal infusion of MSCs promotes retinal ganglion cell (RGC) survival in a mouse model of acute glaucoma, with significantly decreased microglial activation, decreased production of TNF-α, IL-1β, and reactive oxygen species, and reduced caspase-8 and caspase-3 activation. In vitro, MSCs inhibit both caspase-8-mediated RGC apoptosis and microglial activation in part through stanniocalcin 1 (STC1). Furthermore, we found that microRNA-21a-5p (miR-21) and its target, PDCD4, are essential for STC1 production and neuroprotective properties of MSCs in vitro and in vivo. Importantly, our results also demonstrate that miR-21 overexpression or PDCD4 knockdown enhances MSC-induced neuroprotective effects in an acute glaucoma model. These data therefore uncover a previously unrecognized neuroprotective mechanism, by which the miR-21/PDCD4 axis induces MSCs to secrete STC1 and other factors exerting neuroprotective effects. Furthermore, the miR-21/PDCD4 axis is a promising new target for neuroprotection in IOP-induced retinal damage.