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

(2021) 19:194 Li et al. J Nanobiotechnol https://doi.org/10.1186/s12951-021-00940-2 Journal of Nanobiotechnology Open Access RESEARCH Mesenchymal stem cell‑derived extracellular vesicles prevent the development of osteoarthritis via the circHIPK3/miR‑124‑3p/ MYH9 axis Shenglong Li1,2†, Jie Liu3†, Siyu Liu1, Weijie Jiao1 and Xiaohong Wang1,4* 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. Keywords: Mesenchymal stem cells (MSCs), Extracellular vesicles, Osteoarthritis, Circular RNA HIPK3 (circHIPK3), MiR124-3p, MYH9 *Correspondence: ; wangxiaohong@mail. tsinghua.edu.cn † Shenglong Li and Jie Liu contributed equally to this work 1 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 Full list of author information is available at the end of the article Background Osteoarthritis (OA) is a common degenerative disorder of the joints that accounts for major physical pain in older adults [1, 2]. OA could result in severe joint pain, stiffness, limited motion, disability, and in serious cases, the loss of joint mobility [3, 4]. OA is regarded as the leading cause of lower limb disability, with a disability rate of up to 53% [5, 6]. Studies indicate that the incidence of OA increases annually worldwide [7], which not only has a strong impact on the labor ability and quality of life of patients, but also brings a huge economic burden © The Author(s) 2021. This 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://creativeco mmons.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. Li et al. J Nanobiotechnol (2021) 19:194 to society. However, current medical interventions for OA have led to poor clinical outcomes, demonstrating that there are huge unmet medical needs in this area. The occurrence and development of OA are associated with complex interactions among many factors, such as mechanical, cellular, and biochemical factors [8], while the pathogenesis of OA remains unclear. Hence, exploring the novel therapeutic approach for OA is critical. Mesenchymal stem cells (MSCs), a group of multipotential stem cells exhibit self-renewal and tissue differentiation ability, are capable of differentiating into endodermal, mesodermal, ectodermal, and other cell populations in vivo and in vitro [9, 10]. In addition to bone marrow, MSCs are also derived from fat, umbilical cord blood, peripheral blood, placenta, skin, amniotic fluid, synovial membrane, teeth root, and other tissues [11, 12]. MSCs are easy to culture and proliferate in vitro, have strong properties of anti-inflammatory and immunomodulatory, and play a vital role in the repair and regeneration of various tissues [13, 14]. Recently, MSCs have become the most promising seed cell for cartilage repair due to their wide range of sources, less trauma, strong proliferation, and good cartilage differentiation potentials, and have been widely researched and applied [15]. Many studies demonstrate that MSCs from bone marrow, fat and other sources have been applied to clinical treatment of cardiovascular diseases, nervous system diseases, immune diseases, bone and joint diseases [16– 22]. Recently, there has been a notable paradigm shift in the mechanism of action of MSCs in tissue repair. Studies have shown that under specific induction conditions, MSCs cultured in vitro can differentiate into chondrocytes, and the formation of cartilage mimics the development and growth of embryonic cartilage [23]. Different cytokines and growth factors from MSCs, such as insulin-like growth factor (IGF), bone morphogenetic protein (BMP), and transfer growth factor β (TGF-β), have the ability to promote the repair of cartilage tissue [24]. Besides, the anti-inflammatory factors secreted by MSCs and their inhibtion effects on immune cell proliferation play a major role in the repair of OA inflammation [25–29]. Nowdays, more and more studies demonstrate that Nanomaterials play an important role in the process of gene delivery and information exchange [30, 31]. It is increasingly evident that the therapeutic effects of MSCs are largely attributed to their paracrine secretion. The secreted factors, collectively known as the secretome (or secretomes), are composed of soluble proteins, free nucleic acids, lipids, and extracellular vesicles (EVs) [9, 32]. On the basis of biogenesis and size, EVs can be divided into three main types: exosomes (30–150 nm in diameter), microvesicles/microparticles, Page 2 of 20 and a (...truncated)