Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model

Abstract

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease throughout the world. Exosomes derived from miR-140-5p-overexpressing synovial mesenchymal stem cells (SMSC-140s) may be effective in treating OA. We hypothesized that exosomes derived from SMSC-140 (SMSC-140-Exos) would enhance the proliferation and migration abilities of articular chondrocytes (ACs) without harming extracellular matrix (ECM) secretion. METHODS: SMSCs were transfected with or without miR-140-5p. Exosomes derived from SMSCs or SMSC-140s (SMSC-Exos or SMSC-140-Exos) were isolated and identified. Proliferation, migration and ECM secretion were measured in vitro and compared between groups. The mechanism involving alternative Wnt signalling and activation of Yes-associated protein (YAP) was investigated using lentivirus, oligonucleotides or chemical drugs. The preventative effect of exosomes in vivo was measured using Safranin-O and Fast green staining and immunohistochemical staining. RESULTS: Wnt5a and Wnt5b carried by exosomes activated YAP via the alternative Wnt signalling pathway and enhanced proliferation and migration of chondrocytes with the side-effect of significantly decreasing ECM secretion. Highly-expressed miR-140-5p blocked this side-effect via RalA. SMSC-140-Exos enhanced the proliferation and migration of ACs without damaging ECM secretion in vitro, while in vivo, SMSC-140-Exos successfully prevented OA in a rat model. CONCLUSIONS: These findings highlight the promising potential of SMSC-140-Exos in preventing OA. We first found a potential source of exosomes and studied their merits and shortcomings. Based on our understanding of the molecular mechanism, we overcame the shortcomings by modifying the exosomes. Such exosomes derived from modified cells hold potential as future therapeutic strategies.

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

“…In addition, human cardiac progenitor cell‐derived EVs can promote the regeneration of injured heart tissue by increasing the proliferation of cells in/around damaged areas, including cardiomyocytes and endothelial cells, and inhibiting apoptosis of these cells 87. In addition, EVs of non‐nuclear origin, including platelets, also have incredible potential in regenerative medicine 12, 88…”

“…For instance, synovial MSCs can enhance the proliferative and migratory abilities of chondrocytes but also seriously reduce the secretion of extracellular matrix 12. The solution to this problem is to enhance the expression level of miR‐140‐5p in EVs derived from synovial MSCs 12.…”

“…For instance, synovial MSCs can enhance the proliferative and migratory abilities of chondrocytes but also seriously reduce the secretion of extracellular matrix 12. The solution to this problem is to enhance the expression level of miR‐140‐5p in EVs derived from synovial MSCs 12. It is easy to understand that EVs derived from native source cells will not serve as an “omnipotent catholicon” and thus artificial optimization of EVs, with the ultimate aim of modular design of EVs, will be the primary future directions of therapy.…”

“…For example, EVs offer high physicochemical and biological stability,11 which may be due to the isolating ability of the phospholipid layer, protecting the contents of EVs from exposure to the external environment ( Figure 2 ). 12 As a result, EVs can exist in almost all body fluids, including blood plasma,13 saliva,14 urine,15 bile,16 synovial fluid,17 semen,18 and breast milk 19. By expressing different surface proteins, EVs can have different targeting abilities 20.…”

“…However, completely natural EVs may not be sufficient to provide treatments for all kinds of disease conditions; modified EVs have therefore been developed, indicating the beginning of the era of modularized EVs. A variety of modified EVs, including EVs specifically enriched in mRNA,42 miRNA,12, 43 and small interfering RNA (siRNA),20, 44 EVs with membrane modification,45, 46 and EVs carrying small molecule drugs47 and superparamagnetic iron oxide nanoparticles48 have been developed. As the era of personalized and precision medicine continues to develop, the demands of both the targeting ability toward pathological organization combined with limited damage to normal tissues49 to minimize side effects (precision medicine) and freely assembled agents based on a patient's personalized database50, 51 to maximize therapeutic effects (personalized medicine) will continually increase.…”