February 15, 2018

Stem Cell Therapy in Veterinary Medicine

Although this groundbreaking treatment is still in its infancy, anecdotal reports and clinical trials are proving its merits.
By Meredith Rogers, MS, CMPP
Imagine a dog regrowing a limb that had to be amputated after being hit by a car. Salamanders do it—why not dogs?

Urodele amphibians (eg, salamanders and newts) can regenerate complex tissues that are identical to the original in both appearance and function.

Although not fully understood, the process of regeneration occurs as a result of dedifferentiation of the cells at the amputation site into a mass of stemlike cells. This blastema then reforms into all the components of the missing limb: bone, muscle, nerves, and blood vessels.

Stem Cells Explained
Science may not have dogs regrowing lost legs just yet, but a similar premise has driven investigations into stem cell therapy. Stem cells are unspecialized cells with the ability to differentiate into specialized building blocks of organs and tissues. They fall under 2 classifications: embryonic stem cells, derived from 2- to 11-day-old blastocytes, and postnatal stem cells—also called somatic or adult stem cells—found in most adult tissues.

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Whereas embryonic stem cells are totipotent—capable of differentiating into any cell type—adult stem cells are multipotent, capable of differentiating into more than 1 but not all cell types. During normal fetal development, embryonic stem cells differentiate into all the specialized cells necessary for a complete organism, be it a person or a pet. Adult stem cells are normally activated following an injury. Stem cells at the site of the injury self-renew, each undergoing cell division to give rise to a daughter stem cell and a progenitor cell, an intermediate cell type that transforms to the fully differentiated state.

Stem cells for therapeutic uses can be derived from the same animal (autologous), a different individual of the same species (allogeneic), or an animal of a different species (xenogeneic). Adult stem cells can be further categorized as either hemopoietic (derived from core or peripheral blood) or mesenchymal (isolated from the mesoderm layer of different tissues, such as bone marrow, fat, dental pulp, tendons, and skeletal muscle).

Use in Health Care
When used in therapeutic applications, stem cells are generally harvested from bone marrow (femur of dogs and cats, sternum of horses) or adipose tissue (inguinal region of dogs and cats, dorsal surface of the gluteus maximus of horses). Because the fibroblastic phase of tissue healing occurs within a few weeks after an injury is sustained, stem cell therapy is most efficacious when administered during that time frame. Stem cells have been used successfully during the acute inflammatory stage of an injury, but once bone has remodeled or tissue has matured, the utility of stem cell therapy falls significantly.

In both veterinary and human medicine, stem cell therapy has been studied in varied conditions, including cancer, heart disease, immune disorders, Alzheimer and Parkinson diseases, blindness, and diabetes. One of its most widespread uses is in bone marrow transplantation, which has been in regular clinical practice for treating cancer in humans for more than 30 years. In the veterinary world, stem cell therapy has been used primarily in soft tissue injury and wound healing. However, robust clinical trials are few and far between, and most evidence of efficacy comes from anecdotal reports.

Equine Medicine
Tendon and ligament lesions in sport horses are common and often career ending, so stem cell therapy has particular appeal and has received the most attention in that area. Common clinical uses involve treating overstrain injuries of the palmar metacarpal tendons and ligaments.1

In one of the largest studies of stem cell therapy, 113 race-horses with an injury to the superficial digital flexor tendon demonstrated a reinjury rate of 27% after bone marrow–derived mesenchymal stem cell therapy, which was statistically significantly lower than the reinjury rate in historic controls (50%-60%).1 These results were confirmed in a study of dressage and show jumping horses with suspensory ligament desmitis (n = 68) or superficial digital flexor tendon tendinitis (n = 36). The findings showed that 2 years after allogeneic tenogenically induced mesenchymal stem cell therapy was administered 5 days after injury, more than 80% of horses returned to their previous level of performance, and reinjury rates were 18% compared with 44% for conventional treatments.2

In a retrospective chart review of 52 warmblood horses diagnosed with a variety of conditions (such as tendinitis of either the superficial or deep digital flexor tendon, or desmitis of either the suspensory or the inferior check ligament) and treated with allogeneic mesenchymal stem cells derived from umbilical cord blood, 77% returned to work at the same or a higher level.3

Companion Animal Medicine
In companion animals, stem cell therapy is used most often for degenerative disorders. A study of 93 client-owned dogs with osteoarthritis of the hips, elbows, stifles, or shoulders was conducted at sites across the United States.4 After 2 months, dogs treated with allogeneic adipose tissue–derived mesenchymal stem cells exhibited greater improvements in owner-assessed activity and greater decreases in veterinary-assessed pain compared with dogs that received placebo treatment.4 In another randomized study of 39 dogs with hip osteoarthritis, intra-articular adipose tissue-derived mesenchymal stem cell therapy improved function, range of motion, and quality of life, with results maintained at 6 months.5 However, other studies have shown less permanent results.6

Investigatory Uses
Other uses of stem cells that are under investigation for veterinary medicine include treating spinal injuries, cardiac defects, gastrointestinal issues, renal conditions, and bone repair.7,8 Greater functional recovery was observed in dogs that received Matrigel plus neural-induced mesenchymal stem cells 1 week after spinal cord injury compared with dogs that received either phosphate-buffered saline or Matrigel alone.9 A pilot study of 7 cats with chronic enteropathy found that allogeneic adipose–derived feline mesenchymal stem cells improved clinical signs compared with no change or worsening of signs in placebo-treated cats.10

Overall, the procedures have been associated with minimal systemic adverse effects and few local reactions (<1%).11,12 Nevertheless, local pain at the site of injection can be significant, and mild to significant local inflammation has been observed.12

Obstacles to Stem Cell Use
The biggest obstacles preventing more frequent use of stem cell therapy are access and cost. The average small animal veterinary hospital or traveling large animal veterinarian lacks the facilities and expertise to perform these procedures, necessitating referral to a specialty hospital. Thus, veterinarians who do not offer the service should have a relationship with a specialty hospital that offers the procedure by trained staff. In addition, the costs associated with stem cell therapy can be in the thousands. Many horse owners have insurance that usually covers most of the costs associated with treating the initial injury but not subsequent procedures if retreatment is necessary later. However, only a handful of companion animal caretakers in the United States have pet insurance, so for many, the procedure is cost prohibitive. One option could be referral to a clinical trial, as numerous studies on stem cell therapy for a variety of conditions are under way.

If stem cell therapy is determined to be the best course of action for a particular animal, setting realistic expectations with clients is of the utmost importance but can also be one of the hardest discussions to have. Stem cell therapy is still in its infancy, and positive outcomes cannot be guaranteed and may even be elusive or temporary for many that undergo the proce-dure. In addition, even though adverse events are rare, the procedure requires anesthesia, which brings associated risks.

Available Resources
No guidelines currently exist with respect to stem cell therapy, but other resources can aid in making treatment decisions. The North American Veterinary Regenerative Medicine Association was founded as a clearinghouse of related information. The American Veterinary Medical Association has issued a position statement that encourages the study of stem cell therapy but cautions its use in routine clinical practice.13 The FDA recently published its final “Guidance for Industry,” which states that “a cell-based product, including an animal stem cell-based product, that is intended to diagnose, cure, mitigate, treat, or prevent disease in animals, or is intended to affect the structure or function of the animal, generally meets the definition of a new animal drug.”14 This recommendation should promote additional research in order to meet regulatory obligations, providing the evidence needed to validate or dispute stem cell therapy’s widespread use.

Stem cell therapy is emerging as another weapon in the veterinarian’s arsenal, joining the numerous pharmacotherapeutics, sur-gical procedures, and mechanical devices employed to help patients return to full function or at least a more comfortable life.

 
Meredith Rogers has a bachelor of science degree in animal health from the University of Connecticut and a master of science degree in microbiology and molecular genetics from Rutgers University. She has more than 19 years of experience creating content for a variety of health care audiences. She lives in Kingston, New Jersey, and shares her life with a horse, a dog, and a cat.
References:
  1. Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44(1):25-32. doi: 10.1111/j.2042-3306.2011.00363.x
  2. Beerts C, Suls M, Broeckx SY, et al. Tenogenically induced allogeneic peripheral blood mesenchymal stem cells in allogeneic platelet-rich plasma: 2-year follow-up after tendon or ligament treatment in horses. Front Vet Sci. 2017;4:158. doi: 10.3389/fvets.2017.00158.
  3. Van Loon VJ, Scheffer CJ, Genn HJ, Hoogendoom AC, Greve JW. Clinical follow-up of horses treated with allogeneic equine mesenchymal stem cells derived from umbilical cord blood for different tendon and ligament disorders. Vet Q. 2014;34(2):92-97. doi: 10.1080/01652176.2014.949390
  4. Harman R, Carlson K, Gaynor J, et al. A prospective, randomized, masked, and placebo-controlled efficacy study of intraarticular allogeneic adipose stem cells for the treatment of osteoarthritis in dogs. Front Vet Sci. 2016 Sep 16;3:81.
  5. Cuervo B, Rubio M, Sopena J, et al. Hip osteoarthritis in dogs: a randomized study using mesenchymal stem cells from adipose tissue and plasma rich in growth factors. Int J Mol Sci. 2014;15(8):13437-13460. doi: 10.3390/ijms150813437.
  6. Vilar JM, Batista M, Morales M, et al. Assessment of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells in osteoarthritic dogs using a double blinded force platform analysis. BMC Vet Res. 2014;10:143. doi: 10.1186/1746-6148-10-143.
  7. Gade NE, Pratheesh MD, Nath A, et al. Therapeutic potential of stem cells in veterinary practice. Vet World. 2012;5(8):499-507. doi: 10.5455/vetworld.2012.499-507
  8. Marx C, Silveira MD, Beyer Nardi N. Adipose-derived stem cells in veterinary medicine: characterization and therapeutic applications. Stem Cells Dev. 2015;24(7):803-813. doi: 10.1089/scd.2014.0407
  9. Park EH, White GA, Tieber LM. Mechanisms of injury and emergency care of acute spinal cord injury in dogs and cats. J Vet Emerg Crit Care (San Antonio). 2012;22(2):160-178. doi: 10.1111/j.1476-4431.2012.00723.x
  10. Webb TL, Webb CB. Stem cell therapy in cats with chronic enteropathy: a proof-of-concept study. J Feline Med Surg. 2015;17(10):901-908. doi: 0.1177/1098612X14561105
  11. Kang MH, Park HM. Evaluation of adverse reactions in dogs following intravenous mesenchymal stem cell transplantation. Acta Vet Scand. 2014;56:16. doi: 10.1186/1751-0147-56-16
  12. VetStem Regenerative cells— key safety factors. CetStem BioPharma website. vet-stem.com/safety.php. Accessed January 19, 2018.
  13. Therapeutic use of stem cells and regenerative medicine. American Veterinary Medical Association website. avma.org/About/Governance/Documents/2017S_Resolution4_attch.pdf. Accessed January 18, 2018.


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