Regenerative medicine and stem cell therapies hold much promise for the treatment of various injuries and diseases suffered by sportspeople. While there are currently no approved stem cell treatments, researchers are working on harnessing the process by which stem cells repair and replace damaged tissues and cells.
45% of all sports-related injuries are related to muscle contusion and strain. Muscle tissue is comprised of long, tubular cells called myoblasts which fuse to form muscle fibres. Muscle stem cells, also known as satellite cells are responsible for muscle repair. During exercise, muscle fibres become damaged and send signals to satellite cells which sit on top of the muscle tissue. In response to these signals the satellite cells become activated, begin to divide, and as well as making copies of themselves, generate new myoblast cells. These myoblasts are then integrated and repair the damaged muscle tissue. Recently, scientists have discovered that satellite cells from older mice are not able to regenerate muscle as efficiently as those from young mice. This discovery was important as the researchers were able to identify drugs that restored the function of the older cells, and these could be used in future to enhance the repair of muscle tissue
Mesenchymal Stem Cells and Injury Repair
Mesenchymal stem cells (MSCs) are tissue (adult) stem cells which, as well as being able to produce copies of themselves, can divide and form bone, cartilage,muscle, and adipose cells when cultured in the appropriate conditions. MSCs are an attractive resource for researchers and clinicians as they can be readily isolated from a number of patient tissues, including fat. Once obtained and, if necessary, grown-up to high numbers in culture, these MSCs can be re-introduced to the same patient, and therefore there is no risk of immune-rejection. In response to injury, MSCs produce proteins which are suggested to alter the surrounding environment and promote healing and tissue regeneration, such as anti-inflammatory factors, angiogenic factors (which promote the growth of new blood vessels) and other factors which stimulate local, tissue-specific stem cells. Below are some examples of injuries and avenues of research that involve the use of MSCs:
Cartilage has long been thought of as an ideal candidate for cell therapy as it is a relatively simple tissue, composed of one cell type, called chondrocytes, and does not have a substantial blood-supply network. Of most interest to researchers is repair of cartilage tissue in the knee, also called the meniscus of the knee. The meniscus is required to spread the weight of the body at the knee joint when there is movement between the upper and lower leg. Only one third of meniscus cartilage has a blood supply. As the blood supply allows access of healing factors and stem cells attached to the blood vessels (called perivascular stem cells) to the damaged site, this lack of blood supply impairs healing of this tissue. Damage to this tissue is common in athletes, and is the target for surgery in 60% of patients undergoing knee operations, which usually involves the partial or complete removal of the meniscus which can lead to long term cartilage degeneration and osteoarthritis.
In recent times, researchers have increasingly focused on the use of MSCs for treatment of cartilage damage in the knee. There is some data from animal models to suggest that damaged cartilage undergoes healing more efficiently when MSCs are injected into the injury, and this can be further enhanced if the MSCs are modified to produce growth factors associated with cartilage. It has been shown that once the MSCs are injected into the knee they attach themselves to the site of damage and begin to change into chondrocytes, promoting healing and repair. There have been a small number of completed clinical trials in humans using MSCs to treat cartilage damage which have reported some encouraging data, however these studies used very few patients and this makes it difficult to accurately interpret these results. There are currently a number of ongoing trials using larger cohorts of patients, and these may provide more definite information about the role MSCs play in cartilage repair. A number of studies have shown that damaged cartilage can be healed more effectively if the MSCs are delivered in a type of scaffold made from materials which occur naturally in the knee joint. A recent study from the isolated MSCs from patients and seeded these into a collagen scaffold which was then inserted in culture into discs of meniscus tissue which were taken from cows and sheep. Researchers discovered that the MSCs integrated, repaired and stabilised the injured meniscus better than chondrocyte cells. This provided an indication that in the future human MSCs could be used to treat this type of injury.
Tendinopathy refers to injuries that affect tendons – the long fibrous tissues which connect and transmit force from muscles to bones. Tendons become strained and damaged through repetitive use and unsurprisingly, tendinopathy is a common injury among athletes, reported to be linked to 30% of all running-related injuries, while up to 40% of tennis players suffer from some form of elbow tendinopathy or “tennis elbow”. In the UK, each year 85,000 people present with symptoms of Achilles tendinopathy. In this injury, damage occurs to the collagen fibres which make up the tendon, and this damage is repaired by the body through a process of inflammation and production of new fibres which fuse together with the undamaged tissue. However, this process can take up to a year to complete, and results in the formation of a “scar” on the tendon tissue. This scar makes the elastic tendon stiffer and decreases the amount of energy the tissue can store, resulting in a weakening of tendon.
MSCs have the ability to generate cells called tenoblasts which mature into tenocytes. These tenocytes are responsible for producing collagen in tendons. This link between MSCs and collagen is the focus for researchers investigating how stem cells may help treat tendinopathy. Much research has been carried out in racehorses as they suffer from high rates of tendinopathy, and the injury is similar to that found in humans. Researchers found that by injecting MSCs isolated from an injured horse’s own bone marrow into the damaged tendon they could almost halve the reoccurrence of tendinopathy compared to horses that received traditional medical management of this type of injury. A later study by the same group showed the MSCs improved repair resulting in reduced stiffness of the tissue, a decrease in the amount of scarring and better fusion of the new fibres with the existing, undamaged tendon. It should be noted however that it is not yet clear if these results are due to MSCs producing new tenocytes or their ability to modulate the environment around the tendinopathy, as described above. These promising results have paved the way for the first pilot study in humans. Starting in the second half of 2014, researchers will isolate MSCs from the hip bones of tendinopathy patients. These MSCs will be grown-up to high numbers in the lab and patients will receive injections of their own cells at the site of tendon injury.
Bones are unique in that they have the ability to regenerate throughout life. Upon injury, such as a fracture, a series of events occur to initiate healing of the damaged bone. Initially there is inflammation at the site of injury, and a large number of signals are sent out. These signals attract MSCs which begin to divide and increase their numbers. The MSCs then change into either chondrocytes, the cells responsible for making a type of cartilage scaffold, or osteoblasts, the cells that deposit the proteins and minerals that comprise the hard bone on to the cartilage. Finally these new structures are altered to restore shape and function to the repaired bone. A number of studies carried out in animals have demonstrated that direct injection or infusing the blood with MSCs can help heal fractures which previously failed to undergo repair. However, similar to their use in tendinopathy, it is not yet clear if these external MSCs work by generating more bone-producing cells or through their ability to reduce inflammation and encourage restoration of the blood supply to injured bone, or both.
Brain injury in sports
There is mounting evidence that those taking part in sports where they are exposed to repetitive trauma to the head and brain are at a higher risk of developing neurodegenerative disorders, some of which are targets for stem cell treatments. For example, it has been reported that the rate of these diseases, like Alzheimer Disease, were almost four times higher in professional American football players compared to the general population. While the cause of this disease is not yet clear, it is associated with abnormal accumulation of proteins in neural cells which eventually undergo cell death and patients develop dementia. Researchers have attempted a number of strategies to investigate treatments in mouse models of this disease, including introducing neural stem cells which could produce healthy neurons. While some of these experiments have demonstrated positive, if limited, effects, to date there are no stem cell treatments available for Alzheimer’s Disease.
Boxers suffering from dementia pugilistica, a disease thought to result from damage to nerve cells, can also demonstrate some symptoms of Parkinson’s Disease (amongst others). In healthy brains specialised nerve cells called dopaminergic neurons produce dopamine, a chemical which transmits signals to the part of the brain responsible for movement. The characteristic tremor and rigidity associated with Parkinson’s Disease is due to the loss of these dopaminergic neurons and the resulting loss of dopamine production. Researchers are able to use stem cells to generate dopaminergic neurons in the lab which are used to study the development and pathology of this disease. While a recent study reported that dopaminergic neurons derived from human embryonic stem cells improved some symptoms of the disease in mice and rats, there are currently no stem cell treatments for this disease.
Find out more:
- UK Stem Cell Foundation project on Achilles tendinopathy
- BBC article on EPO and doping
- NHS (UK) Sports injury information
- Satellite cells are vital for muscle repair and development - EuroStemCell news article
- International Federation of Sports Medicine - has evidence based guidelines on treatments
- UK Premier League Physio talking about types of knee cartilage damage in footballers [video]