BACKGROUND Retinal pigment epithelium (RPE) cells are potential targets for treating retinal detachment (RD) and proliferative vitreoretinopathy (PVR), considering the importance of neuroprotection and epithelial-mesenchymal transition (EMT) of RPE in these conditions. This study investigated the effect of human Wharton's jelly mesenchymal stem cell secretome (WJMSC-S) on the expression of genes involved in both neuroprotection and EMT in RPE cells in vitro (TRKB, MAPK, PI3K, BDNF, and NGF). METHODS RPE cells from passages 5-7 were treated with WJMSC-S (or the vehicle culture medium as control) for 24 h at 37◦C and subsequently subjected to RNA extraction and cDNA synthesis. Gene expression level was evaluated using real-time PCR in the treated versus control cells. RESULTS The results of our study showed that WJMSC-S led to a significant downregulation in three out of five studied gene expression (MAPK, TRKB, and NGF), and simultaneously, remarkably upregulated the expression of the BDNF gene. CONCLUSIONS According to the present data, WJMSC-S can affect the EMT and neuroprotection processes at the mRNA level by suppressing EMT and promoting neuroprotection in RPE cells. This finding may have positive clinical implications in the context of RD and PVR.