Mesenchymal Stem Cell-Derived Extracellular Vesicles Protect Retina in a Mouse Model of Retinitis Pigmentosa by Anti-inflammation Through miR-146a-Nr4a3 Axis

Retinitis pigmentosa (RP) is a rod-cone degenerative disease that induces irreversible vision loss. Stem cell-derived extracellular vehicles (EVs) have been reported to prevent retinal neurons from apoptosis and inflammation, but the molecular mechanisms remained unclear. Here we probed the ability of mesenchymal stem cell-derived EVs (MSC-EVs) to protect the retinas of RP model mice rd10 and explored the underlying mechanisms. Treatment with MSC-EVs increased the survival of photoreceptors and preserved their structure and visual function. Mechanistically, MSC-EVs suppressed the activation of microglial, Müller glial, macrophages and the NF-κB pathway. MSC-EVs upregulated anti-inflammatory cytokines and downregulated pro-inflammatory cytokines. MSC-EVs application in vitro decreased the number of TUNEL-positive photoreceptor cell line 661W co-cultured with LPS-stimulated glial cell BV2, with similar impact on the cytokine expression as in vivo study. MiR-146a, one of the major miRNAs in MSC-EVs was upregulated in co-cultured cells after MSC-EVs treatment. Upregulation of miR-146a decreased the expression of the transcription factor Nr4a3, and its inhibition promoted Nr4a3 expression in both cells. Nr4a3 was further identified as the target gene of miR-146a. Therefore, MSC-EVs delays retinal degeneration in rd10 mice mainly by its anti-inflammatory effect via the miR-146a-Nr4a3 axis, indicating a strong potential of applying MSC-EVs to treat neurodegenerative diseases. MSC-EVs (MSC-Exo) were injected into the vitreous of rd10 mice at postnatal day 14 (P14) and P21; retinal morphology, function and RNA-seq were examined at P28.