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

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          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.

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          Most cited references85

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          The biogenesis, biology and characterization of circular RNAs

          Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.
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            The expanding regulatory mechanisms and cellular functions of circular RNAs

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              Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs

              Circular RNAs (circRNAs) represent a class of widespread and diverse endogenous RNAs that may regulate gene expression in eukaryotes. However, the regulation and function of human circRNAs remain largely unknown. Here we generate ribosomal-depleted RNA sequencing data from six normal tissues and seven cancers, and detect at least 27,000 circRNA candidates. Many of these circRNAs are differently expressed between the normal and cancerous tissues. We further characterize one abundant circRNA derived from Exon2 of the HIPK3 gene, termed circHIPK3. The silencing of circHIPK3 but not HIPK3 mRNA significantly inhibits human cell growth. Via a luciferase screening assay, circHIPK3 is observed to sponge to 9 miRNAs with 18 potential binding sites. Specifically, we show that circHIPK3 directly binds to miR-124 and inhibits miR-124 activity. Our results provide evidence that circular RNA produced from precursor mRNA may have a regulatory role in human cells.
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                Author and article information

                Contributors
                wangxiaohong709@163.com , wangxiaohong@mail.tsinghua.edu.cn
                Journal
                J Nanobiotechnology
                J Nanobiotechnology
                Journal of Nanobiotechnology
                BioMed Central (London )
                1477-3155
                30 June 2021
                30 June 2021
                2021
                : 19
                : 194
                Affiliations
                [1 ]GRID grid.412449.e, ISNI 0000 0000 9678 1884, Department of Tissue Engineering, Center of 3D Printing & Organ Manufacturing, School of Fundamental Sciences, , China Medical University (CMU), ; No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122 China
                [2 ]GRID grid.459742.9, ISNI 0000 0004 1798 5889, Department of Bone and Soft Tissue Tumor Surgery, , Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, ; Shenyang, 110042 Liaoning Province China
                [3 ]GRID grid.412449.e, ISNI 0000 0000 9678 1884, Department of Prosthodontics, School and Hospital of Stomatology, , China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, ; Shenyang, 110002 China
                [4 ]GRID grid.12527.33, ISNI 0000 0001 0662 3178, Center of Organ Manufacturing, Department of Mechanical Engineering, , Tsinghua University, ; Beijing, 100084 China
                Article
                940
                10.1186/s12951-021-00940-2
                8244143
                34193158
                3533bd67-4211-42cc-823d-ff5132716d25
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 15 May 2021
                : 20 June 2021
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                Biotechnology
                mesenchymal stem cells (mscs),extracellular vesicles,osteoarthritis,circular rna hipk3 (circhipk3),mir-124-3p,myh9

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