Olfactory ensheathing cell-derived extracellular vesicles protect the degenerated retinal pigment epithelium by delivering phagocytosis-related proteins.

Aim: Olfactory ensheathing cells (OECs) are commonly utilized in cell-based therapies for neurodegenerative diseases and central nervous system injuries, due to their unique properties of suppressing gliosis and providing neuroprotection. Small extracellular vesicles (sEVs) have emerged as promising therapeutic agents. This study aimed to investigate OEC-sEVs' effect on retinal degeneration. Methods: Proteomics analysis identified differentially expressed proteins between OEC-sEVs and OECs. We conducted subretinal injection of OEC-sEVs and assessed their protective mechanisms in degenerative retina. Real-time quantitative PCR and Western blot were used to detect the expression of phagocytosis-related molecules in retinal pigment epithelium (RPE) cells. Results: Proteomics analysis revealed that proteins enriched in OEC-sEVs were associated with phagocytosis. Following injection into the subretinal spaces of Royal College of Surgeons (RCS) rats, OEC-sEVs were internalized by RPE cells, leading to the transient upregulation of tyrosine-protein kinase Mer (MerTK), activation of the downstream phosphoinositide 3-kinase/Akt signaling pathway, and restoration of the phagocytic activity of RPE cells towards the photoreceptor outer segments. This delayed photoreceptor degeneration, thereby improving retinal function in RCS rats. In the ARPE-19 cell line treated with the specific MerTK inhibitor UNC2881, enhanced phagocytosis of fluorescent particles and porcine photoreceptor outer segments was observed following OEC-sEV internalization. Conclusion: OEC-sEVs were abundant in proteins associated with phagocytosis, which may partially compensate for the phagocytic deficit of the RPE cells observed in a retinitis pigmentosa rat model via the MerTK-related signaling pathway.