Bone Marrow Mesenchymal Stem Cells Release miR-378a-5p-Carried Extracellular Vesicles to Alleviate Rheumatoid Arthritis

Abstract

This study investigates whether bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) can affect rheumatoid arthritis (RA) by delivering microRNA (miR)-378a-5p to regulate the interferon regulatory factor 1/signal transducer and transcription 1 (IRF1/STAT1) axis. We identified RA-associated miRNAs using the GEO microarray dataset GSE121894. We found the most important miRNAs in RA synovial tissues using RT-qPCR. BMSC-derived EVs were ultracentrifuged and cocultured with human synovial microvascular endothelial cells (HSMECs) in vitro. Dual-luciferase and RNA immunoprecipitation studies examined miR-378a-5p's specific binding to IRF1. We also measured angiogenesis, migration, and proliferation using CCK-8, Transwell, and tube formation assays. Collagen-induced arthritis (CIA) mice models were created by inducing arthritis and scoring it. RA synovial tissues had low miR-378a-5p expression, whereas BMSC-derived EVs had high levels. The transfer of miR-378a-5p by BMSC-derived EVs to HSMECs boosted proliferation, migration, and angiogenesis. miR-378a-5p inhibited IRF1. MiR-378a-5p-containing BMSC-derived EVs decreased STAT1 phosphorylation and HSMEC IRF1 expression. EVs with miR-378a-5p mimic promoted HSMEC proliferation, migration, and angiogenesis, whereas dexmedetomidine inhibited STAT1 phosphorylation. In CIA mice, BMSC-derived EVs containing miR-378a-5p enhanced synovial vascular remodeling and histopathology. Thus, miR-378a-5p from BMSC-derived EVs promotes HSMEC proliferation, migration, and angiogenesis, inactivating the IRF1/STAT1 axis and preventing RA.

Keywords: Extracellular vesicles; Human bone marrow mesenchymal stem cells; Human synovial microvascular endothelial cells; Interferon regulatory factor 1; Rheumatoid arthritis; Signal transducer and transcription 1; miR-378a-5p.