Cartilage Regeneration via EV-associated SulfoTransferase (CREST)

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, inflammation and intra-articular bone osteophyte formation mainly in joints with exceptional wear and tear such as knees, hips, fingers and toes. To regenerate cartilage, approaches such as autologous chondrocyte implantation (ACI) have been developed, in which the patient's chondrocytes are harvested, extracorporeally expanded and reimplanted. A further development is matrix-assisted ACI (MACI), in which implanted cells are held in the defect with a biomaterial membrane made of collagen or hyaluron, thereby supporting the formation of new cartilage. However, the resulting cartilage tissue often has a high collagen content and resembles fibrocartilage or scar tissue rather than functional cartilage. Chondrocytes secrete ECM, which consists of 20~35% solid matrix and 65~80% water, to maintain cartilage function and support tissue regeneration. The solid matrices of the ECM consist of collagen type 2 and proteoglycans, which are heavily modified with glycosaminoglycan (GAG) chains. There are four main classes of GAGs in cartilage, including hyaluronan (HA), keratan sulfate (KS), dematan sulfate (DS) and chondroitin sulfate (CS). CS makes up more than 80 % of the GAGs in articular cartilage and provides gel-like properties such as lubrication, water retention and resilience. Specific sulfotransferases (CHSTs) catalyze the transfer of sulfate groups, resulting in sulfated GAGs (sGAGs), which are essential for the function of cartilage ECM. CHSTs are membrane-bound enzymes and may be present on extracellular vesicles of cartilage cells. The distribution of CHST-EVs in an ECM matrix could therefore promote sGAG synthesis. The biofunctionalization of membranes with these EVs could thus improve cartilage regeneration by producing not only collagen type II but also sGAGs in new cartilage tissue and thus functional cartilage tissue.