مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Wharton’s Jelly MSC-Derived Exosomal microRNAs as Key Modulators of Inflammatory Pathways: An Integrative Bioinformatic Analysis
Wharton’s Jelly MSC-Derived Exosomal microRNAs as Key Modulators of Inflammatory Pathways: An Integrative Bioinformatic Analysis
Elmira Vanaki,1Sahar Shojaei,2Morteza Daliri Joupari,3,*
1. National Institute of genetic engineering and Biotechnology 2. Middle east Gene and cell therapy company 3. National Institute of genetic engineering and Biotechnology
Introduction: Exosomes, nanoscale extracellular vesicles (30–150 nm) secreted by various cell types, have emerged as key mediators of intercellular communication due to their cargo of proteins, lipids, and nucleic acids. Among these, exosomes derived from Wharton’s Jelly mesenchymal stem cells (WJ-MSCs) are gaining significant attention for their potent immunomodulatory and regenerative properties. Unlike parental MSCs, WJ-MSC exosomes are devoid of proliferative risks and immunogenicity, while retaining comparable or superior therapeutic efficacy. A defining feature of these vesicles is their microRNA (miRNA) content, which plays a critical role in regulating inflammation and immune responses. Bioinformatic analyses of WJ-MSC-derived exosomal miRNAs may provide new insights into the molecular mechanisms of inflammation reduction and potential therapeutic applications in chronic inflammatory and degenerative diseases.
Methods: We conducted a comprehensive bioinformatic analysis to identify inflammation-related miRNAs present in WJ-MSC exosomes. Candidate miRNAs were retrieved from curated databases including ExoCarta and miRBase. Target genes were predicted using TargetScan and miRTarBase, followed by functional annotation with DAVID. KEGG pathway enrichment analysis was performed to determine key signaling cascades. Interaction networks between identified miRNAs and target genes were visualized using Cytoscape, emphasizing central hubs in inflammation-associated pathways. Finally, findings were cross-referenced with evidence from preclinical and clinical studies to validate therapeutic relevance.
Results: Four key miRNAs were consistently enriched in WJ-MSC-derived exosomes with strong anti-inflammatory roles: miR-21-5p, miR-146a, miR-181c, and miR-124.
• miR-21-5p and miR-146a emerged as central regulators by suppressing NF-κB and MAPK pathways via targeting TRAF6, IRAK1, and TNF-α.
• miR-181c reduced activation of the TLR4 pathway, thereby downregulating IL-6 and associated cytokines.
• miR-124 targeted STAT3, contributing to suppression of fibrosis and chronic inflammatory cascades.
Network analysis highlighted miR-21-5p and miR-146a as hubs controlling TNF-α and NF-κB activity, while miR-181c and miR-124 were linked to IL-6, TLR4, and STAT3 regulation. KEGG enrichment confirmed significant involvement of the TLR signaling (enrichment score 8.5), NF-κB (7.8), and MAPK pathways (6.9). These findings strongly suggest that exosomal miRNAs orchestrate post-transcriptional regulation of central inflammatory pathways.
Corroborating evidence was observed across preclinical and clinical studies. In osteoarthritis models, intra-articular WJ-MSC exosomes enriched with miR-21-5p and miR-124 reduced MMP-13 and promoted collagen II expression, facilitating cartilage repair. In COVID-19 patients, WJ-MSC exosomes decreased IL-6 and TNF-α serum levels while increasing miR-146a and miR-21-5p expression. Similarly, in ulcerative colitis and systemic lupus erythematosus, exosomal miR-146a and miR-181c dampened inflammatory cell infiltration and T cell hyperactivation. Neuroprotective effects were also observed in multiple sclerosis models, where miR-124-enriched exosomes reduced demyelination and macrophage infiltration. Collectively, these data support the broad therapeutic spectrum of WJ-MSC exosomal miRNAs in modulating pathological inflammation.
Conclusion: This bioinformatic and translational study demonstrates that WJ-MSC-derived exosomal miRNAs are potent regulators of inflammation by targeting critical pathways such as NF-κB, TLR, MAPK, and STAT3. The integration of computational predictions with experimental and clinical data underscores their therapeutic promise in a wide range of inflammatory and degenerative diseases, including osteoarthritis, ulcerative colitis, systemic autoimmune disorders, and neuroinflammatory conditions. These findings pave the way for developing exosome-based, miRNA-guided therapeutic strategies that bridge basic science and clinical application. Moreover, the identification of central hub miRNAs offers opportunities for biomarker discovery and smart drug design. Future work should focus on refining delivery systems, ensuring GMP-compliant production, and validating long-term safety in clinical trials.