Stem Cells in Veterinary Medicine

As pet owners become more interested in advanced treatment options for their pets, they may look to their veterinary team for guidance on the use of stem cells to treat various diseases and injuries. IIn this article we review what is known about stem cells, how they are being used, and how to set reasonable expectations for pet owners.

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Where Are We Now?

by Emily Singler, VMD

Stem cell therapy gained traction in the mid-1990s to early 2000s, when it was first used in the United States for the treatment of ligament injuries in horses and osteoarthritis in dogs. The use of stem cells in both clinical practice and research studies has expanded over the years, and there continues to be cause for hope of further breakthroughs in the use of stem cells to treat diseases in both animals and humans.

As pet owners become more interested in advanced treatment options for their pets, they may look to their veterinary team for guidance on the use of stem cells to treat various diseases and injuries. It can be helpful to review what is known about stem cells, how they are being used, and how to set reasonable expectations for pet owners.

Stem Cells: A Refresher

Stem cells are undifferentiated cells with self-renewal properties and the ability to differentiate into many kinds of cells. They can be derived from many different sites, including embryonic, hematopoietic, and mesenchymal tissues. Embryonic stem cells have the greatest potential for differentiation but come with the highest ethical considerations for use. Hematopoietic stem cells, including those found in cord blood, can be useful for conditions involving immune cells, red blood cells, and platelets.

By far the most used category of stem cell, however, is the mesenchymal stem cell (MSC), which can differentiate into bone, cartilage, ligaments, tendons, fat, skin, muscle, and connective tissues. In veterinary medicine, where stem cells are most often used to treat dogs, cats, and horses, the two sites that have been found to yield the highest quantities of MSCs are bone marrow and adipose (fat) tissue. Because adipose tissue is much more easily harvested than bone marrow, it is often a preferred site for the acquisition of samples.

Although it was initially postulated that stem cell therapy worked by stimulating the formation of new cells in the tissue being treated, subsequent research and clinical trials now suggest that the benefit to stem cell therapy lies in its capacity to modify the immune system and aid in tissue repair (immunomodulation) as well as the ability to migrate throughout the body to the site of disease or injury (homing).

It has been suggested that the name of the cell be changed to “medicinal signaling cell” (still MSC for short) because of the demonstrated ability of these cells to detect injury or tissue damage, travel to the site, and help to coordinate healing of the affected tissue.

Mechanisms of Action

Because more recent studies have shown that stem cells do not replace inflamed, damaged, or diseased cells in the target tissue, it is important to understand how they function and the reasons to consider using them to treat veterinary patients. There are multiple mechanisms by which stem cells may help to heal tissues in various parts of the body. They include paracrine function, extracellular vesicle secretion, immunomodulation through apoptosis, and mitochondria transfer.

Through these mechanisms, MSCs can suppress or change the function of immune cells that can cause inflammation while stimulating wound healing and new blood vessel growth. They can also undergo apoptosis (cell death) when exposed to cytotoxic cells, which draws in macrophages that suppress the inflammatory response in the affected tissue. MSCs have been shown to transfer their mitochondria through nanotubes to diseased cells with nonfunctioning mitochondria. This transfer can enhance the recipient cell’s ability to reduce inflammation and repair tissue.

Clinical Applications

Although stem cells were originally introduced to treat arthritis and other injuries in animals, they are now being used, either experimentally or in practice, for a much wider variety of conditions.

Tendons and Ligaments

Experimentally, MSCs derived from adipose tissue (ADMSCs) or bone marrow (BMMSCs) have been shown to aid the healing of injuries to tendons in horses when injected into the area of the lesion. Instead of producing only fibrous scar tissue, which is not as functional and more prone to reinjury than tendon tissue, horses injected with MSCs were found to have more normal tendon tissue at the site of their previous injury.

In dogs with a ruptured cranial cruciate ligament, intra-articular or IV injections of MSCs after surgical stabilization resulted in anti-inflammatory effects that lasted more than eight weeks after the injection. With partial tears that were not surgically repaired, injections of BMMSCs in combination with platelet-rich plasma helped to prevent progression of degenerative changes in the joint and ligament rupture in the other leg.

Joints

MSCs are effective in treating horses with bone spavin (a degenerative joint disease that causes pain and inflammation) and meniscal damage. The improvement in lameness often lasts at least 90 days after a single injection and sometimes as long as 180 days or more.

Dogs with osteoarthritis have also benefitted significantly from MSC treatment. Intra-articular injections of ADMSCs in dogs with osteoarthritis appeared to have positive effects in terms of reducing pain and lameness that lasted for at least four years in one study.

Progression of arthritic changes in the treated joints also appeared to be delayed when compared with placebo in dogs. In another study, dogs of differing ages with severe osteoarthritis showed improvement in 60% of older dogs and 90% of younger dogs. Very few adverse effects were reported, and those that were reported were mild and self-limiting.

Orodental Diseases

In addition to the bone marrow and adipose MSCs previously described, stem cells have been derived from the dental pulp and periodontal ligament and have been shown in some dog studies to help regenerate the dental pulp and periodontal ligament, respectively. Not all studies have shown a benefit, however, and more research is needed in this area.

In cats, IV injection of MSCs has shown positive results in the treatment of feline chronic gingivostomatitis. ADMSCs were able to cause either complete remission of signs or significant reduction in the severity of the disease in 70% of the treated cats who still had significant disease despite full-mouth extractions. When a smaller study looked at administering ADMSCs to affected cats without extracting any teeth, no benefit was noted.

Digestive Tract Diseases

In patients with inflammatory bowel disease, a single IV infusion of ADMSCs caused clinical remission in 9 out of 11 dogs. These dogs’ albumin, cobalamin, and folate levels were also significantly increased. In cats treated similarly, five out of seven cats were reported to have clinical remission by their owners.

Liver Diseases

In studies, ADMSCs have been used to treat experimentally induced liver cell injury, and IV injections resulted in lowered serum liver enzymes and restored liver tissue structure. IV ADMSC infusions in dogs with liver cirrhosis showed decreased fibrosis in the liver and improved liver function. ADMSCs have also been shown to be beneficial in the treatment of degenerative hepatopathy and hepatocutaneous syndrome.

Renal Diseases

Although single IV injections of ADMSCs did not result in any improvement in cats with chronic kidney disease, repeated IV injections of MSCs sourced from feline amniotic membranes resulted in significantly improved renal function. This was measured by a reduction in serum creatinine levels and urine protein concentrations and an increase in urine specific gravity, along with improvement in clinical signs such as appetite and social interaction.

Cardiac Diseases

Although a study involving the use of MSCs in Doberman pinschers with dilated cardiomyopathy showed no benefits, another small study saw improvement in chronic valvular disease after IV infusion of stem cells derived from deciduous teeth.

Neuromuscular Lesions

For dogs with spinal cord injuries, BMMSCs combined with medication resulted in improved outcomes when compared to medication alone. Likewise, dogs with acute paraplegia because of disc herniation who were treated with ADMSCs through an epidural injection along with surgery had faster improvement than with surgery alone.

Skin Diseases and Wounds

Studies using MSCs in goats, sheep, horses, and dogs have shown improvement in healing of cutaneous wounds. Some of these wounds had been refractory to other forms of treatment. MSCs have also been used to treat atopic dermatitis, but with conflicting results. One study showed no benefit, whereas another showed significant improvement that lasted at least six months.

Eye Diseases

Stem cells have been used to treat refractory corneal ulcers, retinal detachment, and keratitis in horses. In cats, MSCs have shown some promise in treating feline eosinophilic keratitis, and in dogs, they have been effective in treating keratoconjunctivitis sicca (KCS, or dry eye).

Reproductive Diseases

The use of MSCs in horses did not yield any improvement in ovarian function or sperm quality. In dogs, however, the use of extracellular vesicles (ECVs) derived from ADMSCs help reduce the number of sperm damaged during cryopreservation. Additionally, MSCs may help prevent the proliferation of staphylococcus aureus in cows with mastitis, and they may help to repair tissue in goats with mastitis.

Stem Cells in Practice

Valerie Johnson, DVM, PhD, DACVECC, assistant professor of Small Animal Clinic Sciences at Michigan State University College of Veterinary Medicine, has been studying stem cells for more than 10 years. In her role, she harvests stem cells from adipose tissue, bone marrow, or blood and then uses them in clinical trials. She is currently studying the treatment of osteoarthritis in exotic animals and sepsis in sea turtles.

In the past, she has compared intra-articular injections of stem cells in dogs to intra-articular injections of hyaluronic acid. Both resulted in clinical improvement, but there was not much difference between the outcomes of the two treatments. In another study of hers involving IV injection of stem cells in dogs, she demonstrated “improved quality of life and activity” based on validated owner questionnaires. She has also seen great success using stem cells to treat multidrug resistant infections in dogs and to treat elephant endotheliotropic herpesvirus, an often-fatal disease of young elephants.

Take Home Points for Owners

When talking to clients about the benefits of stem cells, Johnson usually tells them that we don’t always know why stem cells work so well in some cases and not in others. She feels comfortable saying that they are safe, although there is a small risk of allergic reaction. But she does always warn owners that she can’t promise that they will help. The more we use them, she says, the more we may improve our understanding of this promising therapy.

It is important for owners who are considering this treatment for their pets to have reasonable expectations. Stem cells appear to help regulate the immune system and support the body to heal itself. This can result in reduced inflammation and pain, more functional tissue, and better quality of life. In some studies, however, stem cells were only found to be helpful in combination with other treatment such as surgery or dental extractions.

Because the stem cells currently used are autologous, meaning they must be harvested from the pet undergoing the treatment, owners must understand that their pet will need a surgical procedure to collect the stem cells. In some cases, this can be done proactively at the time of spay or neuter, and the cells can be saved for possible future use. Studies involving allogeneic stem cells (in which the donor and recipient are not the same animal but of the same species) are ongoing, but for now stem cells must be harvested from the patient in need of treatment.

Fortunately, the future for stem cell treatment looks bright. As research continues, there will likely be many more opportunities to use stem cells to treat conditions beyond arthritis and soft tissue injuries in the clinical setting. What’s more, research in the uses of stem cells in animals will likely lead the way for the use of stem cells in humans to treat a wide variety of conditions. Although stem cells are not a fountain of youth for animals or humans, they may greatly improve the quality of life in animals and help humans and animals live longer and happier lives together.

 

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Emily Singler, VMD, is a 2001 graduate of Penn State University and a 2005 graduate of University of Pennsylvania School of Veterinary Medicine. She has worked in shelter medicine, private practice, and as a relief veterinarian. She currently works as a veterinary writer and consultant and has her own blog, www.vetmedbaby.com

Photo credits: luismmolina/iStock via Getty Images Plus; remotevfx/iStock via Getty Images Plus; wildpixel/iStock via Getty Images Plus; Maksim Tkachenko/iStock via Getty Images Plus; SDI Productions/E+ via Getty Images Plus; luismmolina/iStock via Getty Images Plus

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