Synovial mesenchymal stem cell‐derived extracellular vesicles containing microRN555A‐26a‐5p ameliorate cartilage damage of osteoarthritis

Abstract

Background Osteoarthritis (OA) is a degenerative disease characterized by cartilage damage. We aimed to improve the understanding of the protective mechanism of synovial mesenchymal stem cell (SMSC)‐derived extracellular vesicles (EVs) in cartilage damage of OA. Methods SMSCs and SMSC‐EVs were isolated from synovial biopsies of patients without OA and then identified. The pathological microenvironment of chondrocytes in OA was simulated by inducing SW1353 cells with interleukin (IL)‐1β, followed by SMSC‐EV treatment to assess SW1353 cell proliferation, apoptosis and inflammation. Endocytosis of Dil‐labeled EVs by SW1353 cells was observed. microRNA (miR)‐26a‐5p expression in EVs and EV‐treated SW1353 cells was assessed. The effect of miR‐26a‐5p was evaluated after it was down‐regulated in SMSCs, followed by extraction of EVs, which acted on SW1353 cells. The target relationship of miR‐26a‐5p and phosphatase and tensin homologue (PTEN) was predicted and confirmed. The role of PTEN in OA was evaluated after it was overexpressed. Functional assays were implemented in vivo to certify the role of SMSC‐EVs in OA. Results SMSC‐EVs enhanced IL‐1β‐induced SW1353 cell proliferation, whereas they inhibited apoptosis and inflammation. EVs were endocytosed by SW1353 cells and delivered miR‐26a‐5p into SW1353 cells to overexpress miR‐26a‐5p. Down‐regulation of miR‐26a‐5p in EVs attenuated the protection of EVs against IL‐1β‐induced cell damage. miR‐26a‐5p targeted PTEN, for which overexpression spoiled the protection of EVs against IL‐1β‐induced cell damage. SMSC‐EVs carrying miR‐26a‐5p repaired cartilage damage of OA. Conclusions SMSC‐EVs carried miR‐26a‐5p into chondrocytes to up‐regulate miR‐26a‐5p and inhibit PTEN, thereby inhibiting apoptosis and inflammation and ameliorating cartilage damage of OA.

Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis

“…As for treatment with Exos, injection of miR-9-5p-contained Exos alleviated the inflammation in KOA, which was evidenced by downregulated levels of inflammatory factors and reduced oxidative stress injury [ 110 ]. Lu et al reported synovial MSC-Exos enhanced IL-1β-induced cell proliferation, whereas inhibited apoptosis and inflammation and the target relationship of miR-26a-5p and phosphatase and tensin homologue were predicted and confirmed [ 111 ]. Moreover, Zhe et al investigated miR-26a-5p in human BM-MSCs exerted an alleviatory effect on the damage of the synovial fibroblasts [ 112 ].…”

“…Hu et al revealed that miR-365 expression was activated by chondrogenic induction in both MSCs from the osteoarthritis model and BM-MSCs [ 139 ]. Additionally, some micro-RNAs protect the cartilage, such as miR-26a-5p targeting phosphatase and tensin homolog, miR-26a-5p targeting prostaglandin-endoperoxide synthase 2 [ 111 , 112 ], miR-136-5p targeting E74-like factor 3 [ 101 ], and miR-520d-5p targeting histone deacetylase 4 [ 140 ]. Most reported non-coding RNAs were detected in the Exos, and detailed mechanisms are presented in Table 2 .…”

“…MiR-365 expression was activated by chondrogenic induction in both OA-MSCs and BM-MSCs [ 139 ] Human BM-MSCs-Exos In vitro NR miR-520d-5p/HDAC1 MiR-520d-5p promoted MSCs chondrogenesis and regulates chondrocyte metabolism through targeting HDAC1 [ 140 ] Human BM-MSCs In vitro NR miR-410/Wnt3a MiR-410 was elevated during TGF-β3-induced chondrogenic differentiation of MSCs, and regulated the Wnt signaling pathway [ 135 ] Rat BM-MSCs-Exos Rat NR miR-9-5p/syndecan 1 Anti-inflammatory and chondroprotective effects of BM-MSC-derived exosomal miR-9-5p on KOA via regulation of syndecan 1 [ 110 ] Human BM-MSCs-Exos Rat 250 ng/5 µL miR-26a-5p/Cox2 Human BM-MSC-Exos overexpressing miR-26a-5p serve as a repressor for damage of synovial fibroblasts via Cox2 in KOA [ 112 ] Human SMSCs-Exos Rat 30 µL, 10 11 particles/mL miR-26a-5p/PTEN/IL-1β SMSC-exos enhanced IL-1β-induced cell proliferation, whereas inhibited apoptosis and inflammation. MiR-26a-5p targeted PTEN, for which overexpression spoiled the protection of exosomes against IL-1β-induced cell damage [ 111 ] SMSCs-Exos Mice 5 µL miR-31/KDM2A/E2F1/PTTG1 SMSC-Exos and Exos from miR-31-overexpressed SMSCs alleviated cartilage damage and inflammation in KOA in vivo [ 91 ] Human AT-MSCs-Exos Mice 10 µL, 10 10 particles/mL miR-100-5p/mTOR …”

Culture Condition of Bone Marrow Stromal Cells Affects Quantity and Quality of the Extracellular Vesicles

“…These 88 upregulated miRNAs included miRNAs that have been reported to suppress/inhibit tumor growth and metastasis such as miR-16-2-3p, miR-92b-3p, miR-197-3p, miR-204-5p, miR-320a, miR-411-5p, miR-424-5p, miR-708-5p, miR-718, miR-944, let-7a-5p, and let-7e-5p [52][53][54][55][56][57][58][59][60][61][62][63][64], suggesting that EVs from HPM culture may have superior anti-tumor effects. On the other hand, miRNAs known to protect articular cartilage and enhance cartilage regeneration such as miR-23a-3p, miR-26a-5p, miR-31-5p, miR-100-5p, and miR-140-3p are included in the 46 downregulated miRNAs [44,[65][66][67][68], suggesting that EVs from HPM culture may have less therapeutic effects in the treatment for osteoarthritis. These findings indicate that different culture conditions likely produce EVs with different therapeutic effects.…”

Extracellular Vesicles from Hypoxic Pretreated Urine-Derived Stem Cells Enhance the Proliferation and Migration of Chondrocytes by Delivering miR-26a-5p

“…Jin et al 64 reported that miR-26a-5p from the BMSC-derived exosomes alleviates damage of synovial fibroblasts in OA. Lu et al 65 found that the synovial mesenchymal stem-cells EVs carried miR-26a-5p into chondrocytes to eliminate apoptosis and inflammation in OA. Similarly, we found that after treatment of hypo-EVs, miR-26a-5p was effectively transferred to the target chondrocytes.…”