Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Loaded Mir-451A Targets ATF2 to Improve Rheumatoid Arthritis

OBJECTIVE:Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation, with synovial fibroblasts (SFs) playing a pivotal role in its pathogenesis. Dysregulation of microRNA (miRNA) expression in SFs contributes to RA development. Exosomes (Exos) have emerged as effective carriers for therapeutic molecules, facilitating miRNA transfer between cells. This study explores the therapeutic potential of Exos derived from human umbilical cord mesenchymal stem cells (hUCMSCs), loaded with miR-451a, to modulate ATF2 expression, aiming to address RA in both in vivo and in vitro settings.METHODS:In this study, hUCMSC and RA SFs were isolated and identified, and hUCMSC-Exos were extracted and characterized. The influence of hUCMSC-Exos on RA SFs was detected. And hUCMSC-Exos targeting RA SFs was traced. HUCMSCKD-AGO2 was prepared by knocking down AGO2 in hUCMSC. HUCMSCKD-AGO2-Exos was extracted and characterized,and their influence on RA SFs was detected. The miRNA profiles before and after hUCMSC-Exos intervention in RA SFs were mapped to identify differential miRNAs. RT-qPCR was used to verify the differential miRNAs, with hsa-miR-451a finally selected as the target gene. The effect of miR-451a on SFs was detected. The latent binding of miR-451a to activating transcription factor 2 (ATF2) was analyzed. The effect of hUCMSC-ExosmiR-451a on SFs was detected, and the expression of miR-451a and ATF2 was measured by RT-PCR. In vivo, hUCMSC-ExosmiR-451a was injected into the ankle joint of CIA rats, and arthritis index, joint imaging and synovial pathology were assessed. The expression of miR-451a and ATF2 in synovial tissue was detected. Finally, the safety of hUCMSC-ExosmiR-451a in CIA rats was evaluated.RESULTS:This study revealed that hUCMSC-Exos can inhibit RA SFs proliferation, migration and invasion through miRNAs. High throughput sequencing detected 13 miRNAs that could be transmitted from hUCMSCs to RA SFs via hUCMSC-Exos. miR-451a inhibited RA SFs proliferation, migration and invasion by regulating ATF2. hUCMSC-Exos loaded with miR-451a targeted ATF2 to inhibit RA SFs proliferation, migration and invasion, and improve joint inflammation and imaging findings in CIA rats.CONCLUSIONS:This study demonstrates that miR-451a carried by hUCMSC-Exos can play a role in inhibiting RA SFs biological traits and improving arthritis in CIA rats by inhibiting ATF2. The findings suggest a promising treatment for RA and provide insights into the mechanism of action of hUCMSC-Exos in RA. Future research directions will continue to explore the potential in this field.