Mesenchymal stem cells ameliorate retinal degeneration through modulating microglia during neuroinflammation

Mesenchymal stem cells (MSCs) have been widely reported to be effective in the treatment of neurological diseases including retinal degeneration. MSCs exert their therapeutic effect primarily through promoting neuron survival and reducing neuroinflammation that was mainly dominated by microglia. Due to the heterogeneity of microglia, it is unknown whether MSCs act on all microglia or a particular microglial population during retinal degeneration. After analyzing the characteristic of retinal microglia from the aged mice and the mice with traumatic optic nerve injury (ONI), we found significant retinal microgliosis and identified the microglial population that exist in the retinas from both aged and injured group with the phenotype of antigen-presenting cell (APC). MSC treatment reduced ONI-induced cell death and mitigated reactive gliosis, particularly reduced the population of MHCII+ microglia in injured retina. In vitro experiments showed that MSC could downregulate the expression of CD80, CD86 and MHCII in IFNγstimulated microglia, thus impeding their transition to APCs. MSC treatment did not significantly reduce the proliferation of microglia during inflammation, but we found that MSCs may affect the migration of microglia from the optic nerve into the retina. We found significant increase of chemokine Ccl4 in the retinas from aged mice and ONI mice, and the Ccl4-Ccr5 axis played an important role in mediating the migration of microglia. MSC decreased the expression of Ccl3, Ccl4 in retinas from ONI mice and downregulated Ccl4 expression in the microglia activated by Toll-like receptor (TLR) signaling, both of which contributed to reducing the accumulation of microglia, especially the population with APC phenotype in the degenerating retina