Mesenchymal stem cells (MSCs) have been demonstrated to have promising therapeutic benefits for a variety of neurological diseases;however,the underlying mechanisms are poorly understood.Here,we showed that intravitreal infusion of MSCs promoted retinal ganglion cell (RGC) survival in a mouse model of acute glaucoma,with significant inhibition of microglial activation,production of TNF-α,IL-1β,and reactive oxygen species,as well as caspase-8 and caspase-3 activation.In vitro,MSCs inhibited bothcaspase-8-mediated RGC apoptosis and microglial activation,partly via the action of stanniocalcin 1 (STC1).Furthermore,we found that microRNA-21a-5p (miR-21) and its target,PDCD4,were essential for STC1 production and the neuroprotective property of MSCs in vitro and in vivo.Importantly,miR-21 overexpression or PDCD4 knockdown augmented MSC-mediated neuroprotective effects on acute glaucoma.These data highlight a previously unrecognized neuroprotective mechanism by which the miR-21/PDCD4 axis induces MSCs to secrete STC1 and other factors that exert neuroprotective effects.Therefore,modulating the miR-21/PDCD4 axis might be a promising strategy for clinical treatment of acute glaucoma and other neurological diseases.