Mesenchymal Stem Cell Therapy in Osteoarthritis and Rheumatoid Arthritis: A Systematic Review of Exosomal microRNAs

Seyyed Sina Hejazian,1,2 Seyyedeh Mina Hejazian,3 Seyede Saba Mostafavi Montazeri,4 Sima Abediazar,3 Sepideh Zununi Vahed,3 Abolfazl Barzegari5– 7 1Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 2Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 3Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 4Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran; 5Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; 6Research Center for Pharmaceutical Nanotechnology (RCPN), Tabriz University of Medical Sciences, Tabriz, Iran; 7Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, Université Sorbonne Paris Nord, Villetaneuse, 93430, FranceCorrespondence: Sepideh Zununi Vahed, Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, Email [email protected] Abolfazl Barzegari, Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran, Email [email protected]: Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic diseases characterized by persistent inflammation and autoimmune responses that affect the joints and other organs. Scientific evidence indicates that the therapeutic effects of mesenchymal stem cells (MSCs) are mediated through the release of soluble factors and extracellular vesicles (EVs), particularly exosomes. The release of microRNAs from MSCs holds substantial potential for cell-free treatment in OA and RA.Methods: A comprehensive search was conducted on Web of Science, PubMed, Scopus, and Google Scholar to identify relevant publications until 24 March 2024. The systematic review aimed at illuminating the current understanding of MSC-derived exosomal microRNAs, the origin of MSCs, potential mechanisms of action, and their therapeutic implications in managing OA and RA.Results: A total of fifty-five articles (OA, n= 41 and RA, n= 14) were deemed eligible for inclusion in this study. Regardless of MSC origin, exosomal miRNAs could induce anti-inflammatory, protective, and chondroregenerative potential in in vitro and in vivo models of OA by targeting different signaling pathways. Fourteen studies have highlighted the role of MSC-derived exosomal miRNAs in modulating immune responses, reducing pro-inflammatory cytokine production, and potentially ameliorating synovial inflammation and joint symptoms associated with RA. To suppress joint inflammation and preserve cartilage, miR-140, miR-92a-3p, and miR-136-5p emerged as leading candidates for OA because they help restore the anabolic/catabolic balance and modulate key signaling pathways. For RA, the most effective candidates were miR-146a, miR-150-5p and miR-205-5p that target innate and adaptive immune signaling and synoviocyte activation, with NF-κB modulators such as miR-361-5p offering overlap across both diseases.Conclusion: The mounting body of preclinical evidence supports that MSC-exosomal-miRNAs present a promising solution for OA and RA as a novel therapeutic strategy. However, human studies and more clinical trials are warranted.Keywords: arthritis, extracellular vesicles, miRNAs, stem cells, MSCs, osteoarticular disease