Intra-articular delivery of extracellular vesicles secreted by chondrogenic progenitor cells from MRL/MpJ superhealer mice enhances articular cartilage repair in a mouse injury model

Abstract

Background: Chondrogenic progenitor cells (CPCs) have high self-renewal capacity and chondrogenic potential. Intra-articular delivery of purified mesenchymal stem cells (MSCs) from MRL/MpJ "superhealer" mice increased bone volume during repair and prevents post-traumatic arthritis. Recently, although extracellular vesicles released from MSCs have been used widely for treating OA, the application of extracellular vesicles secreted by CPCs from MRL/ MpJ mice in OA therapy has never been reported. In this study, we evaluated the effects of extracellular vesicles secreted by CPCs from control CBA (CBA-EVs) and MRL/MpJ mice (MRL-EVs) on proliferation and migration of murine chondrocytes. We also determined here if weekly intra-articular injections of CBA-EVs and MRL-EVs would repair and regenerate surgically induced model in mice. Methods: CPC surface markers were detected by flow cytometry. CBA-EVs and MRL-EVs were isolated using an ultrafiltration method. Nanoparticle tracking analysis, transmission electron microscopy, and western blots were used to identify extracellular vesicles. CBA-EVs and MRL-EVs were injected intra-articularly in a mouse model of surgical destabilization of the medial meniscus (DMM)-induced OA, and histological and immunohistochemistry analyses were used to assess the efficacy of exosome injections. We used miRNA-seq analysis to analyze the expression profiles of exosomal miRNAs derived from CBA-EVs as well as MRL-EVs. Cell-counting and scratch assays were used to evaluate the effects of CBA-EVs and MRL-EVs on proliferation and migration of murine chondrocytes, respectively. Meanwhile, a specific RNA inhibitor assesses the roles of the candidate miRNAs in CPC-EV-induced regulation of function of chondrocytes.

Exosomes derived from miR-126-3p-overexpressing synovial fibroblasts suppress chondrocyte inflammation and cartilage degradation in a rat model of osteoarthritis

“…We additionally evaluated the therapeutic utility of isolated SFC-miR-126-3p-Exos in the treatment of ACLT + MMx-induced OA model rats. Intra-articular injection of exosomes can effectively promote cartilage tissue regeneration and prevent OA progression 39 , 40 . We found that administering these exosomes into the articular cartilage was sufficient to suppress OA progression and to enhance the regeneration of cartilaginous tissue, preventing the development of severe damage in these model rats.…”

Extracellular Vesicles in Musculoskeletal Pathologies and Regeneration

“…In fact, CSPCs are thought to be involved in cartilage regeneration as implied by enhanced migratory activity, proliferation and immunomodulatory features after cartilage trauma (Seol et al, 2012 ; Riegger et al, 2018 ). Moreover, it was recently shown that intraarticular application of EVs from murine chondrogenic progenitor cells (CPC) attenuated OA development in a murine destabilization of the medial meniscus (DMM) OA model (Wang et al, 2020 ). Interestingly, CPC-EVs from MRL/MpJ superhealer mice exhibited stronger therapeutic effects as compared to CPC-EVs from non-superhealer mice, which was ascribed to high levels of miRNA 221-3p (Wang et al, 2020 ).…”

“…Moreover, it was recently shown that intraarticular application of EVs from murine chondrogenic progenitor cells (CPC) attenuated OA development in a murine destabilization of the medial meniscus (DMM) OA model (Wang et al, 2020 ). Interestingly, CPC-EVs from MRL/MpJ superhealer mice exhibited stronger therapeutic effects as compared to CPC-EVs from non-superhealer mice, which was ascribed to high levels of miRNA 221-3p (Wang et al, 2020 ).…”

Exosome: A Novel Nanocarrier Delivering Noncoding RNA for Bone Tissue Engineering

“…Exosome miR-128-3p regulates osteogenesis and fracture healing by targeting Smad5 [48]. Decreasing miR-221-3p in exosomes can significantly reduce chondrocyte proliferation and migration in vitro [49]. Exosome miR-17 secreted by keratinocytes can induce osteoclast differentiation [30].…”