• MSC-Derived Extracellular Vesicles in Inflammatory Signaling Pathways and Therapeutic Potential
  • Maryam Heydari,1 Shirin Farivar,2,*
    1. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, 1983969411, Evin, Tehran, Iran
    2. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, 1983969411, Evin, Tehran, Iran


  • Introduction: Mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) have become key mediators of intercellular communication, coordinating a broad range of vital biological functions through the delivery of bioactive cargos to target cells. These membrane-enclosed, nanometre-sized entities, such as exosomes and microvesicles, are a major breakthrough in regenerative medicine, as they provide a promising cell-free therapeutic option that avoids the drawbacks of direct cell-transplantation, including immune rejection and possible tumourigenicity. Uncontrolled and hyperinflammatory response is a key pathogenic characteristic in a wide range of human ailments where traditional anti-inflammatory medications are often ineffective in averting relapses and are associated with a risk of severe side effects.
  • Methods: This review gives a pathway-based synthesis of the mechanisms through which MSC-EVs regulate major inflammatory signalling cascades and methodically examines the effects of MSC-EVs on the NF-κB, JAK/STAT, PI3K/Akt/mTOR and MAPK/ERK pathways, and the NLRP3 inflammasome and Toll-like receptor (TLR) signalling. The therapeutic activity of MSC-EVs is greatly mediated by the various cargo of bioactive molecules, including proteins, lipids, and nucleic acids, including microRNAs (miRNAs), which will be discussed in this review. One of the main mechanisms is inhibition of the Toll-like receptor (TLR)/MyD88/NF-kB signalling pathway; MSC-EVs express miRNAs, including miR-146a, which targets TRAF6 and IRAK1, and miR-125b, which also targets TRAF6, thereby preventing downstream NF-kB activation and thus preventing the release of pro-inflammatory cytokines such as TNF-a, IL-1b and IL-6. The review will also elaborate on the JAK/STAT pathway modulation in which EV-transferred miRNAs including miR-125a and miR-125b suppress the phosphorylation of STAT3, which inhibits the Th17 cell differentiation and enhances an anti-inflammatory regulatory T-cell phenotype. Further, the review will also detail the influence on the PI3K/Akt/mTOR pathway, which is central to the regulation of cell survival and immune tolerance, where EV cargo like miR-100-5p targets mTOR and miR-21 targets PTEN to reestablish cellular homeostasis and tissue repair. Lastly, the review will discuss inhibition of the NLRP3 inflammasome, a multiprotein complex that is important in processing proinflammatory cytokines; MSC-EVs, which carry cargo including miR-17, miR-299-3p and miR-378a, have been shown to inhibit NLRP3 activation and thereby IL-1 and IL-18 maturation and pyroptotic cell death.
  • Results: MSC-EVs have a therapeutic potential that is backed by a large body of preclinical evidence in both acute and chronic inflammatory conditions. MSC-EV-based treatment in acute liver failure and acute kidney injury related to sepsis alleviates inflammatory injury, decreases apoptosis, inhibits the activation of hepatic stellate-cells, and enhances organ recovery. In chronic inflammation models (e.g., inflammatory bowel disease (IBD)) MSC-EVs reduce intestinal mucosal inflammation, promote mucosal healing and improve gut-barrier integrity. They decrease the size of infarcts and stimulate cardiac repair in cardiovascular models, but suppress microglial activation and enhance functional recovery in neuroinflammatory diseases including ischemic stroke. Although MSC-EVs have this therapeutic potential, there are important challenges to clinical translation, which this review analyzes through the lens of translational analysis. One of the major challenges is the creation of standardized scalable procedures of EV production, purification, and characterization to promote uniformity. The natural heterogeneity of MSCs isolated from different tissues and exposed to different culture conditions is an additional cause of batch-to-batch variation, which worsens the reliability of the therapeutic use. This requires the implementation of standardised procedures, as recommended by the International Society of Extracellular Vesicles (ISEV), and the use of scalable purification methods including size-exclusion chromatography (SEC). In addition, regulatory approval and product safety will require the creation of powerful potency assays and identification of key quality attributes. Potential solutions to these obstacles are the use of multi-omics to establish therapeutic signatures and the creation of allogeneic EV therapeutics, which can be stored at room temperature, with low immunogenicity.
  • Conclusion: To conclude, MSC-EVs are a new and innovative next-generation and cell-free therapeutic platform. MSC-EVs have the potential to provide safer and more effective alternatives to traditional therapies by exploiting an in-depth mechanistic insight into their immunomodulatory effects, and by systematically circumventing the current translational challenges, which will bring about a new era in the treatment of inflammatory diseases.
  • Keywords: Mesenchymal Stem Cells, Extracellular Vesicles, Inflammatory Signaling, Regenerative Medicine