After a tendon injury occurs, horses need time off work with a period of box rest. Controlled exercise is then introduced, which is built up slowly to allow a very gradual return to work. This controlled exercise is an important element of the rehabilitation process, as evidence suggests that exposing the tendon to small amounts of strain has positive effects on the remodelling phase of tendon healing. However, depending on the severity of the initial injury, it can take up to a year before a horse can return to racing. Furthermore, when tendon injuries heal, they repair by forming scar tissue instead of regenerating the normal tendon tissue. Scar tissue does not have the same strength and elasticity as the original tendon tissue, and this makes the tendon susceptible to re-injury when the horse returns to work. The rate of re-injury depends on the extent of the initial injury and the competition level that the horse returns to, but re-injury rates of up to 67% have been reported in racing thoroughbreds. The long periods of rest and the high chance of re-injury therefore combine to make tendon injuries the most common veterinary reason for retirement in racehorses. New treatments for tendon injuries aim to reduce scar tissue formation and increase healthy tissue regeneration, thereby lowering the risk of horses having a re-injury and improving their chance of successfully returning to racing.

Over the past 15 years, the use of stem cells to improve tendon regeneration has been investigated. Stem cells are cells which have the remarkable ability to replicate themselves and turn into other cell types. Stem cells exist from the early stages of development all the way through to adulthood. In some tissues (e.g., skin), where cells are lost during regular turnover, stem cells have crucial roles in normal tissue maintenance. However, in most adult tissues, including the tendon, adult stem cells and the tendon cells themselves are not able to fully regenerate the tissue in response to an injury. In contrast, experimental studies have shown that injuries to fetal tissues including the tendon, are capable of undergoing total regeneration in the absence of any scarring. At the Animal Health Trust in Newmarket, we have an ongoing research project to identify the differences between adult and fetal tendon cells and this is beginning to shed light on why adult cells lead to tendon repair through scarring, but fetal cells can produce tendon regeneration. Understanding the processes involved in fetal tendon regeneration and adult tendon repair might enable new cell based and/or therapeutic treatments to be developed to improve tendon regeneration in adult horses.

In many tissues, including fat and bone marrow, there is a population of stem cells known as mesenchymal stem cells (MSCs). These cells can turn into cells such as bone, cartilage and tendon in the laboratory, suggesting that they might improve tendon tissue regeneration after an injury. MSC-based therapies are now widely available for the treatment of horse tendon injuries. However, research has demonstrated that after injection into the injured tendon, MSCs do not turn into tendon cells. Instead, MSCs produce factors to reduce inflammation and encourage better repair by the tissues own cells. So rather than being the builders of new tendon tissue, MSCs act as the foreman to direct tissue repair by other cell types. Although there is some positive data to support the clinical application of MSCs to treat tendon injuries in horses, placebo controlled clinical trial data is lacking. Currently, every horse is treated with its own MSCs. This involves taking a tissue biopsy (most often bone marrow or adipose tissue), growing the cells for 2-4 weeks in the laboratory and then injecting them into the site of injury. This means the horse must undergo an extra clinical procedure. There is inherent variation in the product, and the cells cannot be injected immediately after an injury when they may be the most beneficial.

To allow the prompt treatment of a tendon injury and to improve the ability to standardise the product, allogeneic cells must be used. This means isolating the cells from donor horses and using them to treat unrelated horses. Experimental and clinical studies in horses, mice and humans suggest that this is safe to do with MSCs, and recently an allogeneic MSC product was approved for use in the EU for the treatment of joint inflammation in horses. These cells are isolated from the circulating blood of disease-screened donor horses and are partially turned into cartilage cells in the laboratory. They are then available off the shelf to treat unrelated animals. Allogeneic MSC products for tendon injuries are not yet available, but this would provide a significant step forward as it would allow horses to be treated immediately following an injury. However, MSCs exhibit poor survival and retention in the injured tendon and improvements to their persistence in the injury site, and with a better understanding of how they aid tissue regeneration, they are required to enable better optimised therapies in the future.

Our research has previously derived stem cells from very early horse embryos (termed embryonic stem cells, ESCs. Figure 2). ESCs can grow in the laboratory indefinitely and turn into any cell type of the body. These properties make them exciting candidates to provide unlimited numbers of cells to treat a wide range of tissue injuries and diseases. Our experimental work in horses has shown that, in contrast to MSCs, ESCs demonstrate high survival rates in the injured tendon and successfully turn into tendon cells. This suggests that ESCs can directly contribute to tissue regeneration.

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Outlook for stem cell therapy - its role in tendon regeneration - different treatments for horse tendon injuries - Trainer Magazine