Equine Models for the Investigation of Mesenchymal Stem Cell Therapies in Orthopaedic Disease☆

https://doi.org/10.1053/j.otsm.2016.12.007Get rights and content

Mesenchymal stem cells (MSCs) have emerged as a promising treatment for orthopaedic disease. Well-established equine models of posttraumatic osteoarthritis, focal cartilage healing, and tendonitis provide a platform for testing safety and efficacy of biologic therapies such as MSCs in a species with naturally occurring disease. Horses routinely experience similar conditions that mirror human musculoskeletal injury, including osteoarthritis, meniscal injuries, and Achilles tendinopathy, which provide relevant clinical models for therapeutic interventions. The use of MSCs in equine models of osteoarthritis and focal cartilage healing has yielded encouraging results. When MSCs have been used in equine models of tendonitis or tendonosis, most clinical and experimental studies have been consistently positive. Currently, the relationship among MSC lifespan, persistence within the injured site, administration methods, and treatment efficacy remains unclear, resulting in widespread interest in cell tracking. We conclude that equine models of musculoskeletal disease can provide important preclinical insights into the likely efficacy and mechanisms of activity of MSCs for the treatment of human orthopaedic injuries.

Introduction

Originally, the primary therapeutic activity of mesenchymal stem cells (MSCs), which exhibit pluripotent differentiation capacity, was considered to be through participation in local tissue regeneration.1 However, the current dogma suggests that the primary mechanisms of action of MSCs are the paracrine secretion and cell-to-cell interactions, leading to stimulation of host innate healing mechanisms.2 This article focuses on the importance of equine musculoskeletal disease models, which relate to human disease and what has been learned to date from the use of these models regarding the efficacy and mechanisms of MSC therapeutics.

Section snippets

The Horse as a Model for Orthopaedic Disease in Humans

Small laboratory animals have been used extensively to test MSC use for the treatment of musculoskeletal disease.3, 4, 5 Certainly, a great deal has been learned about cellular therapies from rodent models, but rodents are considered anatomically inferior to equine models in their cartilage thickness, joint size, and joint forces.6, 7 In addition, equine models of tendonitis have been proposed as superior to small animal models because the equine superficial digital flexor tendon (SDFT) is

Equine Posttraumatic Osteoarthritis Model

Equine in vivo models of joint disease include PTOA and models for focal cartilage defects. A PTOA model has been well described in the middle carpal joint of horses.7, 10, 12, 13, 33 This model, through the creation of bone and cartilage debris as well as an osteochondral fragment, results in secondary OA that mirrors clinical disease (racing thoroughbred and quarter horses) and can be effectively monitored by radiographs (Fig. 1).34 The model has been used to test multiple treatments

Equine Models of Focal Cartilage Healing

In a well-accepted and frequently used equine focal cartilage healing model, a critically sized cartilage defect is created on the non–weight-bearing portion of the stifle (the equivalent of the knee joint in humans) (Fig. 2). One to two defects can be created in each lateral (single) or medial (up to 2 defects) trochlear ridge, allowing the horse to serve as its own internal control.40, 41, 42, 43 Monitoring may include, as mentioned previously, lameness examinations, gait evaluation, imaging,

Equine Impact Models of OA

Impact models of joint injury have been developed. An impact model of stifle cartilage degeneration and OA was first described by Bolam et al,47 in which adult horses were subject to arthroscopically induced impact injury to the medial femoral condyle. This injury resulted in microscopic and macroscopic articular cartilage lesions, decreased GAG content in the cartilage and an increase in lameness.47 In addition, a single contusive impact to the palmar aspect of the metacarpus has been

Equine Models of Tendonitis

Models of tendonitis are characterized by their method of lesion induction, as either enzymatically induced or mechanically induced injury. Mechanical models of SDFT injury were first involved in the surgical removal of a window of tendon,50 which has since been replaced by a model in which a central column of tendon is removed.51 Other methods of tendon injury have included transcutaneous radiofrequency coblation,52 or burr-induced mechanical injury.53 Lesions may still be detected grossly,

Localizing MSCs to Sites of Musculoskeletal Injury

Although MSCs appear to aid in soft tissue and cartilage repair, it is unclear how exactly these effects are mediated. As researchers focus on paracrine secretion and the influence of MSCs on the endogenous repair processes,2 investigators have sought to track MSCs after injection to determine the final location of the cells and their overall survival in tissues. Investigators have attempted to evaluate various routes of administration, including intravenous, intralesional, intra-arterial

Clinical Considerations

MSCs may be derived from several sources in horses, including bone marrow, adipose tissues, and umbilical cord tissues. Adipose-derived and bone marrow–derived MSCs are the most thoroughly investigated in the horse.19, 69, 70, 71, 72

Bone marrow can be easily procured in the horse, and may be obtained in a standing, sedated animal from the sternum or ilium. It has been shown that only a small volume (~5 mL) of bone marrow is necessary to maximize the yield of MSCs (compared with 50 mL), with

Regulation of Stem Cell Therapeutics in Animals by the Food and Drug Administration and Center for Veterinary Medicine

In 2015, the Food and Drug Administration issued a guidance (Guidance 218) regarding the evaluation of cell-based products in animals owned as pets or for show or competition, including horses. This guidance excludes animals reared intentionally for research purposes; therefore, the guidance specifically affects clinical research scenarios (clinical trials). The guidance defines cell-based products as “articles containing, consisting of, or derived from cells that are intended for implantation,

Conclusions and Recommendations

The use of cellular therapies involving MSCs for the treatment of musculoskeletal diseases in humans has expanded rapidly in recent years. However, there are a number of key unanswered questions regarding the optimal application of MSCs for these conditions. The equine model of musculoskeletal injury can, therefore, play an important role in addressing some of these questions. In particular, this model may be useful in determining the optimal cell delivery and scaffold material (treatment of

Acknowledgments

The authors would like to thank Dr Sherry Johnson for supplying the data and images for Figure 3.

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    This work was completed at the Orthopaedic Research Center, Colorado State University.

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