Mesenchymal stem cell-derived extracellular vesicles prevent the development of osteoarthritis via the circHIPK3/miR-124-3p/MYH9 axis

Abstract

Background Extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) may play a vital role in a variety of biological processes, including cartilage regeneration. However, few studies reported their potential in the development of osteoarthritis (OA) previously. In this study, we explored the biological roles and underlying mechanism of MSCs-EVs in OA. Results Co-culture experiments revealed that MSCs-EVs could promote the expression of collagen type II alpha 1 chain (COL2A1), SRY-box transcription factor 9 (SOX9) and Aggrecan while negatively regulate the expression of chondrocyte hypertrophy markers matrix metallopeptidase 13 (MMP-13) and RUNX family transcription factor 2 (Runx2) in mouse chondrocytes in the OA model. Besides, the results of cell experiments indicated that MSCs-EVs could notably weaken the suppression of chondrocyte proliferation, migration and the promotion of chondrocyte apoptosis via interleukin1β (IL-1β) induction. In addition, MSCs-circHIPK3-EVs (EVs derived from MSCs overexpressing circHIPK3) considerably improved IL-1β-induced chondrocyte injury. Mechanistically, we elucidated that circHIPK3 could directly bind to miR-124-3p and subsequently elevate the expression of the target gene MYH9. Conclusion The findings in our study demonstrated that EVs-circHIPK3 participated in MSCs-EVs-mediated chondrocyte proliferation and migration induction and in chondrocyte apoptosis inhibition via the miR-124-3p/MYH9 axis. This offers a promising novel cell-free therapy for treating OA. Graphic abstract

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

“…Overexpression of Runx2 partially reversed the effect of the SMSC-155-5p-Exos [ 136 ] MSCs-Exos In vitro, co-culture with mouse chondrocytes NR circRNA_HIPK3/miR-124-3p/MYH9 MSCs-Exos overexpressing circHIPK3 improved IL-1β-induced chondrocyte injury. Mechanistically, circHIPK3 could directly bind to miR-124-3p and subsequently elevate the expression of the target gene MYH9 [ 143 ] Human MSCs In vitro NR lncRNA HOTAIRM1-1/miR-125b/ BMPR2; JNK/MAPK/ERK pathway HOTAIRM1-1 was downregulated in KOA cartilages and may inhibit MSCs viability, induce apoptosis, and suppress differentiation via regulating miR-125b/BMPR2 axis JNK/MAPK/ERK pathway may be a possible downstream mechanism to mediate the role of HOTAIRM1-1 in OA development [ 146 ] Human BM-MSCs-Exos In vitro NR lncRNA HOTTIP/miR-455-3p/CCL3 HOTTIP negatively regulated miR-455-3p and increased CCL3 levels in human chondrocytes [ 147 ] Human AT-MSCs In vitro NR circRNA_ATRNL1/miR‐145‐5p/SOX9 Circ_ATRNL1 regulated the promotion of SOX9 expression to promote chondrogenic differentiation of human AT-MSCs mediated by miR‐145‐5p [ 141 ] Human BM-MSCs-Exos Mice 10 µL, 500 µg/mL circRNA_0001236/miR-3677-3p/Sox9 Exosomal circRNA_0001236 enhanced the expression of Col2α1 and SOX9, but inhibited MMP13 in chondrogenesis via targeting miR-3677-3p and Sox9 [ 142 ] Human BM-MSCs In vitro NR lncRNA GRASLND Silencing of lncRNA GRASLND resulted in lower accumulation of cartilage-like extracellular matrix, while GRASLND overexpression significantly enhanced cartilage matrix production [ 144 ] …”

“…Moreover, circle-RNAs and long non-coding RNAs play vital roles in micro-RNAs interaction and show abnormal expression in osteoarthritis, which may be an important target for regulating osteoarthritis and for drug treatment. These RNAs regulate the progress of KOA by completing with micro-RNAs or other non-coding RNAs, that is called the ceRNA regulatory network, such as circRNA_ATRNL1 targeting miR‐145‐5p [ 141 ], circRNA_0001236 targeting miR-3677-3p [ 142 ], circRNA_HIPK3 targeting miR-124-3p [ 143 ], lncRNA GRASLND [ 144 ], lncRNA MEG3 targeting EZH2-mediated H3K27me3 [ 145 ], lncRNA HOTAIRM1-1 targeting miR-125b [ 146 ], lncRNA HOTTIP targeting miR-455-3p [ 147 ], lncRNA EPB41L4A‐AS1 and lncRNA SNHG7 targeting miR‐146a [ 148 ], and lncRNA LYRM4-AS1 targeting miR-6515-5p [ 149 ].…”

State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis

“…For examples, the treatment of synovial explants with MSC-conditioned media was found that there is the inhibition of the expression of matrix degradative enzymes, including MMP-1, MMP-12, MMP-13, and IL-1β, thus inducing the repair of cartilage tissue [110,127,130]. Another study also pointed toward the character of MSCs to protect chondrocytes via the upregulation of type II collagen production to resynthesize the ECM and decrease the apoptosis via IL-1β downregulation [131,132]. Apart from restoring ECM, the enhanced expression of type II collagen could prevent the hypertrophy of chondrocytes, thus avoiding cartilage degeneration [18,133].…”

Hypoxia-Preconditioned Extracellular Vesicles from Mesenchymal Stem Cells Improve Cartilage Repair in Osteoarthritis

“…Although MSCs have a certain ability to differentiate, studies have shown that the paracrine function of MSCs, especially the secretion of EVs, plays a major role in tissue repair. At present, many preclinical studies have achieved therapeutic effects by using MSC-EVs to treat different diseases, including OA [22]. It is well known that there is a large difference between the oxygen concentration in vivo and in vitro.…”