Mesenchymal stem cell-derived microvesicles confer protection against rheumatoid arthritis-associated interstitial lung disease

BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious condition with few treatment options and a poor outlook. Mesenchymal stem cell-derived microvesicles (MSC-MVs) offer a potential cell-free therapy, but their effectiveness and the role of their miRNA content in RA-ILD are not well understood. METHODS: A mouse model of comorbid RA-ILD was created using collagen-induced arthritis and bleomycin-induced pulmonary fibrosis. Mice received high- or low-dose MSC-MVs via tail vein injection. The treatment effectiveness was evaluated by assessing arthritis severity and pulmonary fibrosis through clinical scores, imaging, histopathology, lung function, and lung coefficients. The expression of fibrotic markers in the lungs was measured using immunohistochemistry and Western blotting. Small RNA sequencing of MSCs-MVs was conducted to explore the underlying mechanism. RESULTS: Administering MSCs-MVs significantly reduced the severity of arthritis and pulmonary fibrosis. Treated mice had better joint and lung scores, with decreased fibrotic areas and lower levels of fibrotic proteins such as anti-α-smooth muscle actin, collagen I, and fibronectin. Small RNA sequencing revealed that MSC-MVs contain microRNAs (miRNAs) (e.g., miR-148a-3p) that target critical pathways in RA-ILD, such as transforming growth factor-β (TGF-β) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. CONCLUSIONS: Our research revealed that MSCs-MVs significantly protect against RA-ILD in a comorbid model. This protective effect is likely facilitated by the transfer of specific miRNAs that modulate essential profibrotic and inflammatory pathways. These results underscore the therapeutic potential of MSC-MVs as an innovative cell-free approach for RA-ILD treatment and identify miRNA-mediated pathway regulation as a pivotal mechanism.