The use of equine chondrogenic-induced mesenchymal stem cells as a treatment for osteoarthritis: A randomised, double-blinded, placebo-controlled proof-of-concept study.

BACKGROUND: There is a need to improve therapies for osteoarthritis in horses. OBJECTIVES: To assess the efficacy of equine allogeneic chondrogenic-induced mesenchymal stem cells combined with equine allogeneic plasma as a novel therapy for osteoarthritis in horses. STUDY DESIGN: Randomised, double-blinded, placebo-controlled experiment. METHODS: In 12 healthy horses, osteoarthritis was induced in the metacarpophalangeal joint using an osteochondral fragment-groove model. Five weeks after surgery, horses were randomly assigned to either an intra-articular injection with chondrogenic-induced mesenchymal stem cells + equine allogeneic plasma (= intervention) or with 0.9% saline solution (= control). From surgery until the study end, horses underwent a weekly joint and lameness assessment. Synovial fluid was collected for cytology and biomarker analysis before surgery and at Weeks 5, 5 + 1d, 7, 9 and 11. At Week 11, horses were subjected to euthanasia, and the metacarpophalangeal joints were evaluated macroscopically and histologically. RESULTS: No serious adverse events or suspected adverse drug reactions occurred during the study. A significant improvement in visual and objective lameness was seen with the intervention compared with the control. Synovial fluid displayed a significantly higher viscosity and a significantly lower glycosaminoglycan concentration in the intervention group. Other biomarkers or cytology parameters were not significantly different between the treatment groups. Significantly less wear lines and synovial hyperaemia were present in the intervention group. The amount of cartilage oligomeric matrix protein, collagen type II and glycosaminoglycans were significantly higher in the articular cartilage of the intervention group. MAIN LIMITATIONS: This study assessed the short-term effect of the intervention on a limited number of horses, using an osteoarthritis model. This study also included multiple statistical tests, increasing the risk of type 1 error. CONCLUSIONS: Equine allogeneic chondrogenic-induced mesenchymal stem cells combined with equine allogeneic plasma may be a promising treatment for osteoarthritis in horses. The Summary is available in Spanish - see Supporting Information.

Allogeneic mesenchymal stem cells improve the wound healing process of sheep skin.

BACKGROUND: Skin wound healing includes a system of biological processes, collectively restoring the integrity of the skin after injury. Healing by second intention refers to repair of large and deep wounds where the tissue edges cannot be approximated and substantial scarring is often observed. The objective of this study was to evaluate the effects of mesenchymal stem cells (MSCs) in second intention healing using a surgical wound model in sheep. MSCs are known to contribute to the inflammatory, proliferative, and remodeling phases of the skin regeneration process in rodent models, but data are lacking for large animal models. This study used three different approaches (clinical, histopathological, and molecular analysis) to assess the putative action of allogeneic MSCs at 15 and 42 days after lesion creation. RESULTS: At 15 days post-lesion, the wounds treated with MSCs showed a higher degree of wound closure, a higher percentage of re-epithelialization, proliferation, neovascularization and increased contraction in comparison to a control group. At 42 days, the wounds treated with MSCs had more mature and denser cutaneous adnexa compared to the control group. The MSCs-treated group showed an absence of inflammation and expression of CD3+ and CD20+. Moreover, the mRNA expression of hair-keratine (hKER) was observed in the MSCs-treated group 15 days after wound creation and had increased significantly by 42 days post-wound creation. Collagen1 gene (Col1α1) expression was also greater in the MSCs-treated group compared to the control group at both days 15 and 42. CONCLUSION: Peripheral blood-derived MSCs may improve the quality of wound healing both for superficial injuries and deep lesions. MSCs did not induce an inflammatory response and accelerated the appearance of granulation tissue, neovascularization, structural proteins, and skin adnexa.

Equine allogeneic chondrogenic induced mesenchymal stem cells: A GCP target animal safety and biodistribution study.

The safety of the intra-articular use of mesenchymal stem cells (MSCs) is scarcely reported. Therefore, the goal of this study was to investigate the safety of a single intra-articular injection with allogeneic chondrogenic induced MSCs combined with equine plasma (=the investigational product: IVP) compared to a saline (0.9% NaCl) placebo control (=control product: CP). Sixteen healthy experimental horses were randomly assigned to receive a single intra-articular injection with either the IVP (n=8) or the CP (n=8) in the left metacarpophalangeal joint. All horses underwent a daily clinical assessment throughout the entire study period of 42days to assess adverse events. Additionally, a local joint assessment and a lameness examination were performed daily during the first two weeks, and weekly the following 4weeks. Blood samples were taken weekly for hematological and biochemical analysis. At the end of the study period, horses of the IVP group were euthanized for a thorough necropsy and to check for biodistribution. Tissue samples of the injected joint were collected for histological examination. In both CP and IVP treated horses a mild transient subjective increase in periarticular temperature and lameness was noted after the intra-articular injection with no significant differences between the treatment groups. No distribution of the cells was found using immunohistochemistry and no ectopic tissue formation or signs of inflammation were found on histology. A single intra-articular injection of allogeneic chondrogenic induced MSCs combined with allogeneic plasma in horses had the same clinical side effects as an intra-articular injection with saline solution.

The effects of equine peripheral blood stem cells on cutaneous wound healing: a clinical evaluation in four horses.

Stem-cell therapy represents a promising strategy for the treatment of challenging pathologies, such as large, infected wounds that are unresponsive to conventional therapies. The present study describes the clinical application of peripheral blood stem cells (PBSCs) for the treatment of four adult Warmblood horses with naturally occurring wounds, which were unresponsive to conventional therapies for at least 3 months. A visual assessment was performed, and a number of wound-healing parameters (granulation tissue, crust formation and scar formation) were evaluated. In all cases, tissue overgrowth was visible within 4 weeks after PBSC injection, followed by the formation of crusts and small scars in the centre of the wound, with hair regeneration at the edges. In conclusion, this is the first report of PBSC therapy of skin wounds in horses, and it produced a positive visual and clinical outcome.