Therapeutic potential of stem cell-derived extracellular vesicles in osteoarthritis: preclinical study findings

Kim et al. Laboratory Animal Research (2020) 36:10 https://doi.org/10.1186/s42826-020-00043-3 Laboratory Animal Research REVIEW Open Access Therapeutic potential of stem cell-derived extracellular vesicles in osteoarthritis: preclinical study findings Ki Hoon Kim1, Jeong Hyun Jo1, Hye Jin Cho2, Tae Sub Park1,2 and Tae Min Kim1,2* Abstract Extracellular vesicles (EVs) are nano-sized particles secreted by almost all cell types, and they mediate various biological processes via cell-to-cell communication. Compared with parental cells for therapeutic purposes, stem cell-derived EVs have several advantages such as reduced risk of rejection, less oncogenic potential, ease of longterm storage, lower chance of thromboembolism, and readiness for immediate use. Recent studies have demonstrated that EVs from stem cells, mostly from mesenchymal stem cells (MSCs) from various tissues, have antiinflammatory, anti-oxidative, anti-apoptotic, and proliferative role in injured organs including osteoarthritic lesions. Herein, we provide a review about the up-to-date studies in preclinical application of stem cell-derived EVs in osteoarthritis animal arthritis models. Keywords: EVs (extracellular vesicles), MSCs (Mesenchymal stem cells), OA (osteoarthritis) Introduction Among joint diseases, osteoarthritis (OA) is one of the most severe types of arthritis that is caused by loss of joint cartilage and bone [1]. Mostly, the articular damage is due to loss of self-repair capability of injured cartilage caused by mechanical stress, e.g., sudden or unadjusted movements, mechanical injury, excess weight, loss of muscle strength supporting joint, and damage in peripheral nerves [2]. Also, it is still under debate whether exercise increases the risk of osteoarthritis in the knee [3]. Osteoarthritis: its pathophysiology So far various soluble mediators have been reported to be involved in the progression of OA. Readers are referred to other reviews on the detailed role of the role of pro-inflammatory (IL-1β, TNF-α, IL-6, IL-17) (Fig. 1) * Correspondence: 1 Graduate School of International Agricultural Technology, Pyeongchang, South Korea 2 Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354, South Korea and anti-inflammatory cytokines that are involved in OA pathogenesis (IL-4, IL-10, IL-13) [4, 5]. For example, an elevated level of IL-1β and TNF-α was found in OA synovial fluid, synovial membrane, and subchondral bone cartilage [6]. Mechanistically, these cytokines down-regulated the synthesis extracellular matrix (ECM) component by inhibiting anabolic activities of chondrocytes. Another study showed that IL-1β reduces the expression of the type II collagen, which is a major ECM component constituting the cartilaginous tissues in several animal species [7, 8]. Also, the expression of Aggrecan, which is one of the major components of the cartilage, was found to be decreased by IL-1β treatment in chondrocytes and cartilage [9]. Indirectly, IL-1β and TNF-α stimulate chondrocyte to produce a proteolytic enzyme such as matrix metalloproteinases (MMPs), including MMP-1 (interstitial collagenase), MMP-3 (stromelysin 1), MMP-13 (collagenase 3) [10–12]. In addition, ADAMTS (a disintegrin-like and metalloproteinase with thrombospondin motifs) of is also one of the major players in cartilage degradation in OA. 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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. Kim et al. Laboratory Animal Research (2020) 36:10 Page 2 of 7 Fig. 1 The role of proinflammatory cytokines in the pathophysiology of OA. The role of proinflammatory cytokines, including IL-1β, TNF-α, IL-6 and IL-17, are elevated in OA. These cytokines contribute to the pathogenesis of OA through several mechanisms including downregulation and upregulation of inflammatory responses. Abbreviations: ADAMTS: a disintegrin-like and metalloproteinase with thrombospondin motifs; IL: interleukin; MMP: matrix metalloproteinase; NO: nitric oxide; TNF: tumor necrosis factor reported that the expression of ADAMTS-4 can be induced by IL-1β and TNF-α, while the expression of ADAMTS-5 was not affected [13]. In contrast, subsequent study has shown that IL-1β induced its mRNA expression in rabbit nucleus [14]. Other than these proteases, miR30a was also shown to play an important role in controlling ADAMTS-5 expression that was caused by IL-1β [15]. Also, IL-1β and TNF-α induce the generation of inflammatory cytokines such as IL-6 [14] and IL-8 [16], monocyte chemoattractant protein 1 (MCP1) [17] and CC-chemokine ligand 5 (CCL5) [18], all of which are well-reported players in sustaining tissue inflammation. IL-6 exists at a low concentration level in normal chondrocyte. However, its concentration in sera and chondrocytes is increased in osteoarthritic condition, after which it causes the increases in IL-1β and TGF-β, which in turn they promoted the production of IL-6 [19, 20]. Studies also demonstrated that IL-6 stimulates the expression of MMP-1 and MMP-13 in bovine and humans (cell type) [21, 22], and IL-6 reduced the expression of type II collagen (cell type) [23]. Other studies showed that the expression of IL-17 is upregulated by IL-1β, TNF-α and IL-6, after which IL-17 upregulated NO and MMPs production [24]. In addition, IL-17 led to a reduced expression of proteoglycan [25]. Current treatment method for OA Depending on the disease status, clinical protocols can be classified into surgical method, using NSAIDs (Nonsteroidal anti-inflammatory drugs), via physical therapy, opioids, or intra-articular injection of hyaluronic acid (Fig. 2). Although NSAIDs have been commonly used for relieving inflammation due to their analgesic and anti-inflammatory effect, side effects such as the organ toxicity (e.g., liver and kidney) have been critical. In particular, using NSAIDs for a long-term or repeated time can lead to gastrointestinal tract hemorrhage [26–28]. Thus, other alter (...truncated)