Osteoarthritis (OA) has emerged as a prevalent condition causing pain and physical disability among the elderly population [1]. Currently, pain management and physiotherapy are still the first-line treatment for early OA. However, these approaches cannot alter the progression of early OA, and when the disease progresses to the end stage, ultimately leading to arthroplasty as the only option [2]. Therefore, alternative therapies that relieve symptoms and slow the progression of early OA are pressing needed.

In the past decade, intra-articular injection of autologous blood-derived products to manage early OA has been broadly investigated [3,4]. Platelet-rich plasma, a blood product prepared by centrifugation of autologous blood, is the most commonly used in orthopedics to reduce the pain and inflammation of the joint, as well as repair the cartilage defect in OA. Although the exact mechanism is complicated and not clear yet, the therapeutic effect of blood derivatives is now believed to be attributed to the various growth factors and cytokines released from platelet degranulation, which promote cartilage regeneration in OA [[5], [6], [7]]. Although the blood derivatives exerted remarkable therapeutic effect in the animal model, however, the high-quality evidence provided by large-scale randomized controlled trials found that intra-articular injection of autologous blood derivatives did not benefit the elderly patients with early to moderate OA in both symptom control and structure progression when compared to those receiving saline placebo injection [8,9]. Recent research also reported serum from old mice showed no effect on the aged skeletal tissue. In contrast, the serum from young mice effectively rejuvenated the aged skeletal stem cells and promoted muscle regeneration [10]. Taking together, the blood derivatives extracted from old individuals seem to be ineffective in treating degenerative disease due to the disappearance of regenerative factors with aging.

Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures allowing cells to exchange proteins, lipids and genetic material [11]. A recent study reported that EVs derived from plasma duplicate the therapeutic power of blood derivatives in promoting cell proliferation, migration and osteogenic differentiation of bone mesenchymal stem cells [12,13]. Noticeably, researchers highlight that the beneficial effect of young serum on tissue regeneration disappeared following the removal of its EVs, providing robust evidence that EVs dominate in the rejuvenating effect of blood derivatives [10]. Compared to blood derivatives, EVs even possess a higher amount of several growth factors including basic fibroblast growth factor, vascular endothelial growth factor, platelet-derived growth factor and transforming growth factor beta 1, which are widely accepted as the functional components of blood derivatives [12,14]. In addition to enriched growth factors, EVs also contain abundant mRNAs, microRNAs and other bioactive contents, while these substances are also believed to play an essential role in tissue regeneration [15,16]. Thus, young human plasma-derived EVs might provide an alternative approach to promoting cartilage regeneration for elders with OA.

Although it is well demonstrated that blood-derived EVs from youngsters are more effective than those from elders in activating skeletal stem cells, the difference between blood-derived EVs from young and old individuals on chondrocytes remains undetermined. Therefore, we first evaluated young human plasma-derived EVs (YEVs) with EVs from old human plasma-derived EVs (OEVs) utilizing chondrocytes in vitro to explore their differences in cartilage repair. We found that YEVs effectively promoted chondrocyte proliferation and migration, while OEVs provided limited benefit to chondrocytes in vitro. Accordingly, we further determine whether YEVs could still play a role in chondroprotection and chondrogenesis in the circumstance of OA.