Extracellular vesicles — new tool for joint repair and regeneration

Abstract

Cell-derived extracellular vesicles (EVs), present in synovial fluid and cartilage extracellular matrix (ECM), are involved in joint development and in the regulation of joint homeostasis. Although the exact function of EVs in these processes remains incompletely defined, the knowledge already acquired in this field suggests a role for these EVs as biomarkers of joint disease, and as a new tool to restore joint homeostasis and enhance articular tissue regeneration. In addition to direct injection of therapeutic EVs into the target site, surface coating of scaffolds and embedding of EVs in hydrogels might also lead to novel therapeutic possibilities. Based on the existing literature of EVs in synovial fluid and articular tissues, and investigation of the molecular factors (including microRNAs) active in joint homeostasis (or during its disturbance), we postulate novel perspectives for the implementation of EVs as a regenerative medicine approach in joint repair.

Figure 1. Proposed mechanisms of EV‑mediated communication in inflammatory joint disease.

During local inflammation, infiltrating leukocytes (T cells, B cells, monocytes, monocyte-derived macrophages) and resident synovial macrophages activate fibroblast-like synoviocytes (FLSs) in the synovial membrane by extracellular vesicle (EV)-mediated cell-to-cell communication. Activated FLSs further maintain inflammation by production of cytokines and enzymes. By the release of their own EVs, FLSs signal back to immune cells and enzyme-loaded, FLS-derived EVs can invade aggrecan-rich extracellular matrix (ECM). Leukocyte-derived EVs can carry factors that cause local hypercoagulation. Activated-platelet-derived EVs cause IL-1 receptor-mediated activation of FLSs and can be internalized by activated neutrophils, maintaining the inflammatory phenotype of the two cell types. B cells recog-nize citrullinated proteins in EV-immune complexes, which might be part of the autoimmune process in rheumatoid arthritis. AP1, activator protein 1; CCL2, C–C motif chemokine 2; CCL5, C–C motif chemokine 5; COX-2, cyclooxygenase 2 (prostaglandin G/H synthase 2); DC, dendritic cell; HA, hyaluronic acid; ICAM, intercellular adhesion molecule; JNK, c-Jun N-terminal kinase; MMP, matrix metalloproteinase; PGE, prosta-glandin E; mPGES-1, microsomal prostaglandin E synthase 1; sPLA₂-IIA, secreted phospholipase A₂-IIA; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor.

Figure 2. Proposed applications of EVs in joint disease.

a | Extracelluar vesicles(EVs) have bio-marker potential for joint diseases, both to predict disease development in healthy individuals and to monitor disease progression in patients. In the blood, circulating inflammatory EVs can be an alert for early onset of inflammatory joint diseases. In synovial fluid, EVs from patients can provide information about inflammation type, disease state and disease progression. In the context of tissue biopsies, EVs derived from cultured synovial tissue could indicate predisposition for development of autoimmune disease and cartilage disorders. b,c | Regulatory EVs can be exploited for intra-articular injection or for application in biomaterials designed for implantation purposes to restore joint homeostasis and improve tissue repair in patients. BMP, bone morphogenetic protein;|GF-1, insulin-like growth factor 1; iPSC, induced pluripotent stem cell; miRNA, microRNA; MSC, mesenchymal stem/stromal cell; PDGF, platelet derived growth factor; TGF-β, transforming growth factor-β.