Large animal models have been widely used to facilitate the translation of mesenchymal stem cells (MSC) from the laboratory to patient. MSC, with their multi-potent capacity, have been proposed to have therapeutic benefits in a number of pathological conditions. Laboratory studies allow the investigation of cellular and molecular interactions, while small animal models allow initial 'proof of concept' experiments. Large animals (dogs, pigs, sheep, goats and horses) are more similar physiologically and structurally to man. These models have allowed clinically relevant assessments of safety, efficacy and dosing of different MSC sources prior to clinical trials. In this review, we recapitulate the use of large animal models to facilitate the use of MSC to treat myocardial infarction-an example of one large animal model being considered the 'gold standard' for research and osteoarthritis-an example of the complexities of using different large animal models in a multifactorial disease. These examples show how large animals can provide a research platform that can be used to evaluate the value of cell-based therapies and facilitate the process of 'bench to bedside'. Keywords Mesenchymal stem cell. Large animal. Osteoarthritis. Myocardial infarction 'large' animal models). An animal is considered a 'large animal' when the species in question is non rodent, rabbit or guinea pig (Thomas et al. 2012). The more commonly used large animal models in research include horses, cows, pigs, sheep, goats, primates and dogs, and the choice of animal model depends on multiple factors, including

Objective Mesenchymal stem/stromal cells (MSCs) and MSC‐derived extracellular vesicles (MSC‐EVs) have been reported to alleviate pain in patients with knee osteoarthritis (OA). We undertook this study to determine whether MSCs and/or MSC‐EVs reduce OA pain through influencing sensory neuron excitability in OA joints. Methods We induced knee OA in adult male C57BL/6J mice through destabilization of the medial meniscus (DMM) surgery. Mice were sorted into 4 experimental groups with 9 mice per group as follows: unoperated sham, untreated DMM, DMM plus MSC treatment, and DMM plus MSC‐EV treatment. Treated mice received either MSCs at week 14 postsurgery or MSC‐EVs at weeks 12 and 14 postsurgery. Mouse behavior was evaluated by digging and rotarod tests and the Digital Ventilated Cage system. At week 16, mouse knee joints were harvested for histology, and dorsal root ganglion (DRG) neurons were isolated for electrophysiology. Furthermore, we induced hyperexcitability in DRG neurons in vitro using nerve growth factor (NGF) then treated these neurons with or without MSC‐EVs and evaluated neuron excitability. Results MSC‐ and MSC‐EV–treated DMM‐operated mice did not display pain‐related behavior changes (in locomotion, digging, and sleep) that occurred in untreated DMM‐operated mice. The absence of pain‐related behaviors in MSC‐ and MSC‐EV–treated mice was not the result of reduced joint damage but rather a lack of knee‐innervating sensory neuron hyperexcitability that was observed in untreated DMM‐operated mice. Furthermore, we found that NGF‐induced sensory neuron hyperexcitability is prevented by MSC‐EV treatment (P < 0.05 versus untreated NGF‐sensitized neurons when comparing action potential threshold). Conclusion MSCs and MSC‐EVs may reduce pain in OA by direct action on peripheral sensory neurons.

This systematic review examines the current literature regarding surgical techniques for restoring articular cartilage in the hip, from the older microfracture techniques involving perforation to the subchondral bone, to adaptations of this technique using nanofractures and scaffolds. This review discusses the autologous and allograft transfer systems and the autologous matrix-induced chondrogenesis (AMIC) technique, as well as a summary of the previously discussed techniques, which could become common practice for restoring articular cartilage, thus reducing the need for total hip arthroplasty. Using the British Medical Journal Grading of Recommendations, Assessment, Development and Evaluation (BMJ GRADE) system and Grade system. Comparison of the studies discussed shows that microfracture has the greatest quantity and quality of research, whereas the newer AMIC technique requires more research, but shows promise.Cite this article: W. E. Hotham, A. Malviya. A systematic review of surgical methods to restore articular cartilage in the hip. Bone Joint Res 2018;7:336–342. DOI: 10.1302/2046-3758.75.BJR-2017-0331.

Recent environmental sampling around a landfill site in the UK demonstrated that unidentified xenoestrogens were present at higher levels than control sites; that these xenoestrogens were capable of super-activating (resisting ligand-dependent antagonism) the murine variant 2 ERβ and that the ionic liquid 1-octyl-3-methylimidazolium chloride (M8OI) was present in some samples. To determine whether M8OI was a contributor to the xenoestrogen pool in the soils, activation of human estrogen receptors by M8OI was examined. M8OI activated the human ERα in MCF7 cells in a dose-response manner. These effects were inhibited by the ER antagonist ICI182780; occurred in the absence of any metabolism of M8OI and were confirmed on examination of ER-dependent induction of trefoil factor 1 mRNA in MCF7 cells. M8OI also super-activated the murine variant 2 ERβ in a murine hepatopancreatobiliary cell line. The human ERβ was not activated by M8OI when expressed in HEK293 cells. These data demonstrate that M8OI is a xenoestrogen capable of activating the human ERα and super-activating the murine variant 2 ERβ.

Background: Osteoarthritis (OA) in the horse is an economic and welfare issue and there are no current disease modifying drugs available. Stem cells have been suggested as a therapeutic intervention for OA, originally on the basis of their regenerative capacity. However, it is hypothesised that mesenchymal stem cells (MSC) exert their effects via paracrine factors including the production of extracellular vesicles that can themselves recapitulate the MSC effects in the joint. Objectives: To isolate extracellular vesicles from bone marrow MSC and investigate their anti-inflammatory effects on chondrocytes. Study design: An in vitro assessment of the effect of direct culturing extracellular vesicles on artificially inflamed chondrocytes. Methods: Extracellular vesicles were isolated from bone marrow MSC using differential sequential ultracentrifugation. Vesicles were characterised using electron microscopy, nanoparticle tracing analysis and protein analysis. Vesicle internalisation was carried out via vesicles being pre-stained and co-cultured with equine chondrocytes before analysis using confocal microscopy. The effects of vesicles on artificially inflamed chondrocytes was examined using quantitative PCR. Results: To the best of the authors' knowledge, this is the first study to isolate and characterise extracellular vesicles from equine bone MSC. Vesicles were taken up by autologous chondrocytes and had anti-inflammatory effects on gene expression following chondrocyte exposure to tumour necrosis factor α and Interleukin 1β. Main limitations: Only three independent biological repeats were performed and the work was done in vitro. Conclusion: Extracellular vesicles can be isolated from equine bone marrow MSC; they may be taken up by chondrocytes and have an anti-inflammatory action.

Background Osteoarthritis (OA) in the horse is an economic and welfare issue and there are no current disease modifying drugs available. Stem cells have been suggested as potential therapeutics for OA, originally on the basis of their regenerative capacity. However, it is now hypothesised that MSCs exert their effects via paracrine factors including the production of extracellular vesicles, that can themselves recapitulate the MSC effects in the joint. Results In this study we have, for the first time, isolated and characterised extracellular vesicles from equine bone marrow stem cells. We have shown these vesicles can be taken up by autologous chondrocytes and have anti-inflammatory effects on gene expression following chondrocyte exposure to tissue necrosis factor α and Interleukin 1β. No effects on chonodrocyte proliferation or migration was observed. Conclusion Extracellular vesicles can be isolated from equine bone marrow mesenchymal stem cells, they are taken up by chondrocytes and have an anti-inflammatory action.