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Large-Scale Preparation of Synovial Fluid Mesenchymal Stem Cell-Derived Exosomes by 3D Bioreactor Culture
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IL-27-induced, MSC-derived Exosomes Promote MMP3 Expression Through the miR-206/L3MBTL4 Axis in Synovial Fibroblasts

Lihui Ma, Yueli Liu, Fenghuang Xu

    Alternative Therapies in Health and Medicine
    |September 7, 2023
    PubMed
    Abstract

    Insights

    Interleukin-27 (IL-27) induces mesenchymal stem cell (MSC) exosomes that promote matrix metalloproteinase 3 (MMP3) expression in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). This occurs via the miR-206/L3MBTL4 axis, worsening joint damage.

    Area of Science:

    • Immunology and Rheumatology
    • Cell Biology and Extracellular Vesicles
    • Molecular Biology and Gene Regulation

    Background:

    • Rheumatoid arthritis (RA) involves fibroblast-like synoviocytes (FLS) secreting matrix metalloproteinases (MMPs), leading to chondrocyte destruction.
    • Mesenchymal stem cells (MSCs) influence FLS via extracellular vesicles (EVs).
    • Interleukin-27 (IL-27), an immune regulator, is often overexpressed in RA.

    Purpose of the Study:

    • To investigate the effects of IL-27-induced exosomes derived from bone-marrow MSCs (BM-MSCs).
    • To determine if these exosomes promote matrix metalloproteinase 3 (MMP3) secretion in synovial cells.

    Main Methods:

    • Genetic study involving co-culturing IL-27-induced MSCs with FLS.
    • Analysis of IL-27 expression in synovial fluid.
    • Detection of MMP3 expression, miRNA profiling (including miR-206-3p), and target gene identification (L3MBTL4) using qRT-PCR, Western blot, dual luciferase, and ChIP assays.

    Main Results:

    • IL-27 was highly expressed in RA synovial fluid.
    • IL-27-induced MSC-derived exosomes significantly upregulated MMP3 expression in FLS.
    • The miR-206-3p/L3MBTL4 axis was identified as the mechanism by which exosomes promote MMP3 transcription, leading to chondrocyte degradation and RA exacerbation.

    Conclusions:

    • IL-27 induces miR-206 expression in MSCs, which is transported via MSC-EVs to FLS, promoting migration and MMP3 expression, thus aggravating articular cartilage damage.
    • Patients with high IL-27 expression may not benefit from standard MSC therapy.
    • MSCs with knocked-down or deleted IL-27 receptor (IL-27R) could be a potential therapeutic strategy for RA patients with high IL-27 levels.

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