Tendon injuries are common in both veterinary and human clinical patients and result in morbidity, pain, and lost athletic performance. Consequently, utilizing naturally occurring injuries in veterinary patients as a comparative model could inform the development of novel therapies and increase translation for the treatment of human tendon injuries. Mesenchymal stem cells (MSCs) have shown considerable efficacy for the treatment of experimental and clinical superficial digital flexor tendon injury in the horse; however, the reinjury rate following treatment can remain high and MSC efficacy in treating other tendons is less well known. Additionally, the translation of MSC therapy to human tendon injury has remained poor. Recent evidence indicates that naïve MSC function can be enhanced through exogenous stimulation or manipulation of their environment. This stimulation or activation, herein termed MSC licensing, markedly alters MSC functions associated with immunomodulation, extracellular matrix remodeling, vascular development, bioactive factor production, and endogenous stromal/progenitor cell support. Additionally, a variety of licensing strategies has proven to influence MSC-secreted factors that have positively influenced outcome parameters in both in vitro and in vivo disease models separate from musculoskeletal tissues. Therefore, identifying the optimal licensing strategy for MSCs could ultimately provide an avenue for reliable and repeatable treatment of a broad range of tendon injuries of both veterinary and human clinical patients. This article details current evidence on the effects of licensed MSCs in both in vitro and in vivo disease models of different species and provides commentary on how those effector functions identified may be translated to the treatment of tendon injuries.
The purpose of this manuscript, which is part of the Currents in One Health series, is to take a comparative approach to stem cell treatment for tendon injury and consider how the horse might inform treatment in other veterinary species and humans. There is increasing experimental and clinical evidence for the use of bone marrow–derived mesenchymal stem cells to treat tendon injuries in the horse. The same evidence does not currently exist for other species. This manuscript will review why the equine superficial digital flexor tendon core lesion might be considered optimal for stem cell delivery and stem cell interaction with the injury environment and will also introduce the concept of stem cell licensing for future evaluation. The companion Currents in One Health by Koch and Schnabel, AJVR, October 2023, addresses in detail what is known about stem cell licensing for the treatment of other diseases using rodent models and how this information can potentially be applied to tendon healing.
Objective—To determine the effects of matrix metalloproteinase (MMP)-13, compared with interleukin (IL)-1α, on cartilage matrix molecule gene expression in a coculture system of equine cartilage explants and synoviocytes.
Sample Population—Articular cartilage and synovium specimens harvested from femoropatellar joints of 4 horses, aged 3 to 5 years.
Procedures—Synoviocytes were isolated and cocultured with cartilage explants. Cultures were treated with human recombinant MMP-13 (1, 25, or 100 ng/mL) or IL-1α (0.01, 0.1, 1.0, or 10 ng/mL) for 96 hours, with medium exchange at 48 hours. Cartilage extracts and media were analyzed for glycosaminoglycan (GAG) content, and results were adjusted to cartilage DNA content. Quantitative PCR was performed on mRNA from cartilage (MMP-3, MMP-13, aggrecan, and collagen type IIB [COL2A1]) and synoviocytes (MMP-3 and MMP-13), and results were adjusted to 18S ribosomal subunit mRNA expression. Treatments were performed in triplicate, and the experiment was repeated 4 times.
Results—Cultures treated with MMP-13 or IL-1α had increased media GAG concentration at 48 and 96 hours. Aggrecan and COL2A1 mRNA expression were increased by application of MMP-13 or IL-1α. Gene expression of the catabolic mediator, MMP-3, in cartilage and synoviocytes was increased in cultures treated with MMP-13 or IL-1α. Expression of MMP-13 mRNA in cartilage was increased by IL-1α, but decreased in synoviocytes by MMP-13 treatment.
Conclusions and Clinical Relevance—Results support the use of recombinant MMP-13 in a coculture system of synoviocytes and cartilage explants for the study of osteoarthritis.
Limb lymphedema in horses can be debilitating and painful. Pneumatic compression therapy has shown significant benefits for people suffering from lymphedema. The objective of this study was to determine the effect of a novel, equine-specific pneumatic compression device on the lymphatic flow of healthy horse forelimbs as determined by Tc-99m sulfur colloid lymphoscintigraphy.
6 healthy Thoroughbreds.
In a randomized crossover design, horses underwent bilateral forelimb lymphoscintigraphy following subcutaneous injection of Tc-99m sulfur colloid at the coronary band as untreated control or with pneumatic compression therapy using the EQ Press. Lateral, static images were obtained of the distal limb (time 0 to 60 minutes) and proximal limb (time 30 to 60 minutes) using a standard gamma camera. Lymphatic flow was determined by assigning a score to the time point at which Tc-99m sulfur colloid was first visualized at the level of the accessory carpal bone (1 to 7) in the distal limb and the cubital lymph node (1 to 4) in the proximal limb.
EQ Press treatment led to a significantly faster lymphatic flow of Tc-99m sulfur colloid to the predetermined anatomic locations of the accessory carpal bone (P = .002) in the distal limb and the cubital lymph node (P = .001) in the proximal limb.
Pneumatic compression therapy as provided by an equine-specific device encouraged lymphatic flow in healthy, nonedematous equine forelimbs. These data support further study of the EQ Press for pneumatic compression therapy in horses clinically affected by lymphedema and lymphatic drainage disorders.
Recent state and federal legislative actions and current recommendations from the World Health Organization seem to suggest that, when it comes to antimicrobial stewardship, use of antimicrobials for prevention, control, or treatment of disease can be ranked in order of appropriateness, which in turn has led, in some instances, to attempts to limit or specifically oppose the routine use of medically important antimicrobials for prevention of disease. In contrast, the AVMA Committee on Antimicrobials believes that attempts to evaluate the degree of antimicrobial stewardship on the basis of therapeutic intent are misguided and that use of antimicrobials for prevention, control, or treatment of disease may comply with the principles of antimicrobial stewardship. It is important that veterinarians and animal caretakers are clear about the reason they may be administering antimicrobials to animals in their care. Concise definitions of prevention, control, and treatment of individuals and populations are necessary to avoid confusion and to help veterinarians clearly communicate their intentions when prescribing or recommending antimicrobial use.