Stem cell‐derived extracellular vesicles attenuate the early inflammatory response after tendon injury and repair

Abstract

Adipose‐derived stem cells (ASCs) have the potential to enhance tendon repair via paracrine regulation of the inflammatory response to injury. Extracellular vesicles (EVs), which are secreted by ASCs, have shown promise in mediating this process. This study was designed to evaluate the effect of ASC EVs on early tendon healing using a mouse Achilles tendon injury and repair model. EVs were isolated from the conditioned medium of naïve and interferonγ‐primed ASCs and applied to the repair site via a collagen sheet. Tendon healing was assessed in nuclear factor‐κB (NF‐κB)‐luciferase reporter mice up to 7 days after suture repair. As anticipated, repair site NF‐κB activity increased greater than twofold following tendon repair. Treatment with EVs from primed but not naïve ASCs effectively suppressed the response. Accordingly, the pro‐inflammatory genes Il1b and Ifng were both dramatically increased in repaired tendons, while primed, but not naïve ASC EVs attenuated the response. Compared with control repairs, primed ASC EVs further reduced the rate of post‐repair tendon gap formation and rupture and facilitated collagen formation at the injury site. Additional experiments demonstrated that EVs target macrophages and that primed ASC EVs were most effective in blocking macrophage NF‐κB activity. Collectively, the findings of this study demonstrate that primed ASC EVs, similar to ASCs, attenuate the early tendon inflammatory response after injury via modulation of the macrophage inflammatory response. Statement of clinical significance: These findings introduce a new cell‐free therapy, derived from stem cells, for tendon repair with the potential for improved therapeutic efficacy and safety. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:117–127, 2020

Extracellular vesicles from rat-bone-marrow mesenchymal stromal/stem cells improve tendon repair in rat Achilles tendon injury model in dose-dependent manner: A pilot study

“…Higher concentrations of MSC-derived EVs performed better than low concentrations and better than MSCs alone. As already shown [9,10,11], three studies have already been published on this topic, but direct comparisons with the present investigations are difficult given the different focus. The three previous studies focused largely on inflammatory mechanisms, and used different methodologies and different types of injury over different time periods.…”

“…Cell-free delivery of bioactive cargos by EV induces the same beneficial responses as stemcell transplantation, offering remarkable benefits over conventional cell-therapy: for example, EVs avoid the risk of tumorigenesis, and heterotopic ossification and calcification [3,4] and are immunologically unresponsive agents [7,8]. Finally EVs play a role in tendon-healing by modulating inflammatory responses [9,10,11].…”

Proteomics identifies differences in fibrotic potential of extracellular vesicles from human tendon and muscle fibroblasts

“…Treatment of tenocytes in a number of in vitro and in vivo experimental models with EVs from various sources, e.g. plasma [ 14 ], adipose stem cells [ 15 ], tendon progenitors [ 16 ], macrophages [ 17 ], have demonstrated that signalling through EVs can modulate the expression of genes that regulate ECM synthesis and remodelling. Exosomes derived from tendon cells have also been reported [ 18 , 19 ]; and one study showed that tendon cell-derived exosomes induce the expression of tenogenic genes in bone marrow-derived mesenchymal stem cells in a TGFβ-dependent manner [ 19 ].…”

Extracellular Vesicles from Mesenchymal Stem Cells as Novel Treatments for Musculoskeletal Diseases

“…EVs also have the potential to enhance tendon repair via paracrine regulation of the inflammatory response to injury [154]. In a model of Achilles tendon healing after unilateral surgical transection, AD-MSC EVs were loaded to the surface of a collagen sheet which was applied around the repair site.…”

“…In a model of Achilles tendon healing after unilateral surgical transection, AD-MSC EVs were loaded to the surface of a collagen sheet which was applied around the repair site. This treatment attenuated inflammatory cell migration and NF-κB activation whereas the anabolic response was facilitated leading to tendon matrix regeneration [154]. Another possible strategy consists of polarizing macrophages to an M2 phenotype by incubating these cells with EVs from human BM-MSCs.…”