I’ve written about stem cell therapies numerous times over the years, though not for quite a while. My conclusions were always along the lines of “promising but unproven.” This is one of those perfectly plausible therapies that I expect will be beneficial at some point but which has, like so many conventional and alternative treatments, has been rushed into use well before we have sufficient evidence to know what it can really do and what it can’t.
I have recently written an update on the topic, and not a great deal has changed since I first covered it over a decade ago. There is much more research evidence, but the variety of types of treatments tested and the different conditions and measures of effect used make it difficult to confidently asses the effectiveness of any specific stem cell treatment on the market for any specific problem. Overall, the evidence is still promising but unproven, though it has gotten at least a little better for the most common use, osteoarthritis. Despite this, there is a long way to go before we can recommend stem cell treatments without a lot of caveats about the uncertainty for their benefits and for long-term safety.
Leaping Before Looking
Science can be frustrating. There is always a gap between having a great idea and having a new tool to change things in the real world. Ideally, that gap is bridged by robust, rigorous scientific research which tells us whether the original idea is really as great as it seems and what it will actually let us accomplish. Even in the best case, filling the gap between inspiration and real-world change takes time. And all too often, seemingly good ideas crack under the pressure of scientific investigation and fail to live up to their promise.
Our natural human tendency is to let our excitement over a new discovery or hypothesis to carry us away, and to start implementing our new ideas as quickly as possible. If we’re lucky, that lets us achieve the change we want to make in the world more quickly. Unfortunately, in most cases the result is less positive. Skipping past the process of interrogating new hypotheses scientifically commonly leaves us with tools that don’t work, or that have harmful effects we didn’t anticipate. Nature is inevitably more complex that our ideas about it, and enthusiasm can’t overcome the gap between what we think we understand and the reality of the natural world.
In veterinary medicine, we are always seeking new understandings and new tools to better care for our patients. Compared to our colleagues in human medicine, we are relatively unconstrained in trying out our ideas. As I discussed in my last essay, regulatory oversight of veterinary medicine is light, and we are accustomed to therapies with little supporting evidence and to leaping into new practices well before they have built the kind of supportive evidence required in human medicine.
This is a necessary evil given the limited resources available to build better evidence in veterinary medicine. When our ideas turn out to be right, we have the advantage of getting effective treatments to our patients faster and with less cost than in human medicine. When we are wrong, of course, we end up exposing our patients to therapies that seem like they should work but are actually ineffective (e.g. tramadol, glucosamine, homeopathy) or harmful (e.g. high-dose steroids for spinal cord injury, treatment of asymptomatic bacteriuria with antibiotics).
One of the most exciting ideas I have watched develop over my twenty years as a veterinarian is the hypothesis that stem cell therapies can be used to treat a great variety of different health problems in veterinary patients. Stem cells have been a subject of intense enthusiasm, controversy, and research in human medicine for several decades, and this has spilled over into veterinary medicine, with the usual time delay and lower level of available evidence. In an example of the potential benefits from the looser regulatory burden in our field, stem cell therapies are being also explored in our patients as a springboard for more rapid development and approval of treatments for humans.
As often happens, preliminary research in laboratory animals and in human medicine led to relatively rapid commercialization and clinical use of stem cell treatments in veterinary medicine well before robust clinical trial evidence in companion animals with natural disease had been developed. Fortunately, as better evidence has been slowly accumulated, it is looking more and more like we may have “guessed right” in this case, and that the risks to our patients are minimal (though not negligible) and there may well be meaningful benefits. Regulatory approval of commercial veterinary stem cell therapies is just beginning, and I am hopeful that despite our cart-before-the-horse approach to this treatment, therapies which are demonstrably safe and effective may be available soon. However, as a recent review of the science in this field concluded, “despite considerable advancements in veterinary regenerative
medicine in recent years, this field is still in its infancy and much more work is needed to resolve many questions before proven, standardized therapies [can] be offered to the clinical patients.”1
What Are Stem Cells?
Stem cells possess the ability to differentiate into a variety of cell types.1 The degree of differentiation present in a stem cell and the potential for further replication and differentiation varies among different kinds of stem cells. Pluripotent trophoblasts present in the early embryo can give rise to a complete organism, while stem cells present in adults have considerably less potential to differentiate.2 Early stem cell research focused on embryonic cells derived from fetal tissue, but social and political controversy around this led to the predominance of mesenchymal stem cells (MSC) derived from adult tissues as the focus of research into potential stem-cell therapies.3 It is also possible to induce fully-differentiated adult cells to become pluripotent stem cells through genetic manipulation, though there are potential safety concerns to such methods which are still being investigated.1,2,4
Early hypotheses about the medical benefits of stem cell use centered on the idea that these cells could be introduced into diseases tissue where they would differentiate into needed cell types. For example, if a dog has a damaged cranial cruciate ligament or degraded articular cartilage, intra-articular stem cell injection could produce new connective tissue or cartilage to replace the damaged tissues. This is now understood to be incorrect, and the mechanisms by which exogenous stem cells influence disease are more complex and indirect.
Stem cells have significant immunomodulatory effects, exerting paracrine influence on a variety of cells via cytokines and mediators of inflammation and growth. MSCs can also influence apoptosis of other cells, and they appear to be able to exchange extracellular vesicles and even mitochondria with endogenous cells.1,2 There is a great deal still to be learned about how exogenous stem cells function and what physiologic effects they have when administered to veterinary patients. These details are critical to rational use of these cells as clinical treatments, and failing to appreciate this complexity is likely to lead to ineffective therapy.
Finally, stem cell therapies can be categorized based on their origins. As already mentioned, they may be embryonic, induced pluripotent adult cells, or mesenchymal stem cells, which are most commonly used in veterinary medicine. MSCs can also be taken from the patient we intend to treat (autologous), from another donor individual of the same species (allogenic), or even from a donor of a different species (xenogenic). Each of these sources has different potential risks and benefits.
Autologous stem cells are most commonly used in commercial treatments available today. This is largely due to regulatory constraints. The Food and Drug Administration (FDA) has indicated that while the agency considers stem cell therapies to be animal drugs under the law, and therefore theoretically an FDA license is required for their use, they choose to employ discretion in enforcement. Specifically, the FDA allows use of autologous stem cell products under a set of specific conditions:
- The product is minimally manipulated.
- The product is for homologous use.
- The product is for use in nonfood-producing animals.
- The manufacture of the product does not involve the combination of the cells with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new safety concerns with respect to the product.
- The finished product is not combined with or modified by the addition of any component that is a drug or device.
Allogenic stem cells do not meet these criteria and so require FDA licensing for use, which is a significant burden in terms of time and cost, and this has encouraged regenerative medicine companies to focus on autologous products.
In theory, autologous stem cells should have minimal risk since they are derived from the patient in which they are used. However, the complexity of stem cell behavior and the potential for changes in these cells with isolation and handling after harvesting means there is still some potential for adverse effects.1
One disadvantage to autologous stem cell therapies is the need for harvesting of tissue (usually fat) from the patient under sedation or anesthesia. This is followed by isolation of MSCs and then administration of these cells to the patient, often with another procedure under sedation or anesthesia depending on the route of administration. Patients who are ill or cachectic or who cannot tolerate the delay between harvesting and administration of the therapy may not be good candidates for this process.
Commercial, ready-to-use allogenic stem cell therapies would obviate the need for harvesting MSC form the patient and allow faster, more standardized treatments. Because of their capacity to multiply, stem cells harvested from a single healthy donor could be used to produce therapies for many patients. The major impediments to this approach are the regulatory requirements for demonstrating safety and efficacy and the inherently greater potential for harm in giving tissue from one individual to another. However, the benefits of allogenic tissue donations can outweigh the risks, as is often the case for common practices such as blood transfusion. If this proves true for allogenic MSC therapies, there would be significant advantages compared to the currently more common autologous products.
What Can Stem Cells Be Used For?
The potential benefits of stem cell therapies are many.1,2,5 The most commonly studied involves administering stem cells to support tissue healing and regeneration. Stem cells may be useful in reducing pain and disability associated with osteoarthritis, promoting healing of wounds, and even supporting development of nervous system tissues to restore function lost after nerve damage. Typically, MSCs are delivered directly to the site of injury to support healing and regeneration. However, our growing understanding of stem cell activities and effects has raised the possibility of less intuitive uses.
For example, MSCs have also been shown to exhibit homing, a chemotactic behavior in which they migrate to sites of tissue injury.1 This opens the possibility of treating diseases through systemic administration of MSCs rather than local delivery. This is a significant advantage when local administration is not safe or practical, as in patients unable to tolerate anesthesia or in organs it may be difficult to administer stem cells to directly, such as the heart or kidneys. The paracrine and other effects of MSCs on endogenous cell activity may allow for treatment of inflammatory and autoimmune diseases and other indications beyond straightforward tissue regeneration.
There are, of course, technical challenges to such applications, such as the difficulty ensuring MSCs get to the target tissue and the complex and the sometimes unpredictable interactions between such exogenous cells and the body of the recipient. It is also important to bear in mind that many specific uses for stem cell therapies are largely hypothetical, will little or no reliable evidence to validate them.
What is the Evidence?
As I suggested earlier, stem cell therapies are an example of a promising idea that was turned into commercial products and rushed into clinical use in veterinary patients use well before adequate research evidence was available to establish the true risks and benefits. I have been quite critical of this field in the past, and while better supporting evidence is gradually accumulating, it is still disappointing that so many veterinary patients have received largely unproven stem cell therapies.
The International Society for Stem Cell Research (ISSCR) has warned human patients for many years that most stem cell therapies marketed to them are not scientifically validated. Apart from bone marrow transplantation and the use of stem cells in some tissue grafting procedures, there are no stem cell therapies approved for use in humans. While the FDA applies similar standards to regulation of veterinary and human stem cell therapies, including a relatively permissive attitude towards autologous treatments, it has warned manufacturers of stem cell therapies for both animal and human patients against marketing products or making claims that are not consistent with the regulatory limits the agency has set. Unapproved stem cell treatments have cause serious injury to human patients6, and while there are few reports of harm in veterinary patients,7 this is likely due as much to a lack of reporting and surveillance as to a lack of actual harm.
The veterinary stem cell industry has proven profitable, with estimates in the tens of millions of dollars and projections for growth into the hundreds of millions in the near future. One of the major companies in the field, VetStem, reports first using its stem cell therapy in dogs in 2004. By 2020, the company claimed 30,000 of its treatments had been given. FDA approval for this therapy, however, is still “expected” sometime in 2022. Though manufacturers of veterinary stem cell therapies and others have conducted some studies, it is difficult to justify such extensive use of multiple different stem cell treatments without even the minimum standard of FDA approval, much less a robust base of replicable clinical trial evidence showing the safety and efficacy of specific therapies. Only one veterinary stem cell therapy has received official regulatory licensure, a product for use in horses in the European Union.
The research literature concerning stem cell therapies is large and varied. There are in vitro and lab animal studies, studies in humans, and clinical trials in veterinary species, mostly horses and dogs. These studies cover many different types of both autologous and allogenic treatments for numerous medical conditions.1,2,5 Each type of evidence, and every specific study, has particular strengths and limitations, and a comprehensive review is beyond the scope of this article. The most robust evidence, and the most common use for stem cell therapies in small animals, involves osteoarthritis in dogs, so I will focus on that subject. This is a fair representation of the best companion animal stem cell research has to offer as well as the still significant gaps in the evidence.
There have been some relatively good quality studies, with randomization, blinding, and control groups, for both autologous and allogenic stem cell therapies for arthritis in dogs.8–10 The strongest of these compared intra-articular injection of an allogenic stem cell product and saline in 74 dogs using subjective measures of pain and function from both owners and veterinarians.8 The study found an expected placebo effect but also significantly greater improvement in most outcome measures for the treatment group.
A smaller study of 21 dogs compared an autologous adipose-derived product with saline injected into the hip joints of arthritic dogs.9 In general, blinded subjective assessments by veterinarians showed improvement in measures of pain and lameness for both groups, with the treatment group improving more than the control. Owner assessments also showed more improvement in treated dogs than in the placebo group, though the differences were not statistically significant. Another study by the same group using the same product in 14 dogs with elbow arthritis also reported improvement in both veterinary and owner assessments, but no control group or blinding was reported.11
Other studies have had less robust methodology. One, for example, showed improvement with autologous MSC treatment in 8 dogs with severe hip arthritis on some objective measures of weight bearing, but the control dogs were healthy and were not treated with a placebo.10 Another study evaluated an allogenic stem cell therapy in over 200 dogs and reported dramatic improvements.12 However, there was no control group or other control for bias in this study, which render the results potentially unreliable.
A study of an autologous adipose-derived MSC treatment in 10 dogs with osteoarthritis of the knee show some clinical improvement but no change in radiographic appearance or synovial fluid composition compared with a saline placebo.13However, there is no reported information about blinding or other important bias control methods and no statistical analysis, making the reliability of the findings difficult to assess.
A trial investigating allogenic adipose-derived MSCs given as an intra-articjular injection to 30 dogs with elbow arthritis followed the dogs for a year and reported significant improvements. Again, unfortunately, the results of an uncontrolled and unblinded study such as this cannot support confident statements about efficacy.14
In addition to placebos, stem cell therapies have been compared to other regenerative treatments such as platelet rich plasma (PRP, which I have discussed previously).15 In one study, 31 dogs were randomized to an adipose-derived autologous MSC treatment or PRP and evaluated on a number of measures of pain and function by veterinarians and owners. There were statistically significant improvements in both groups, though the changes were sometimes small in magnitude, and the MSC group appeared to improve more than the PRP-treated dogs. The lack of a placebo control is a limitation in this study.
Far less plausible uses for stem cell therapies in arthritic dogs have been studied, such as the injection of MSCs at acupuncture points to treat hip arthritis.16 Apart from the numerous problems with acupuncture in general, this study also failed to include blinding, placebo controls, or other methods necessary to produce reliable and clinically useful research evidence.
These studies illustrate that while there is some encouraging evidence for stem cell treatments in dogs with osteoarthritis, and even a few quite persuasive studies,8,9 the research is often at high risk of bias and error and lacking the sample sizes and methodological rigor needed for confidence in therapeutic claims. The research evidence for other applications of this technology is no better, and often it is quite a bit weaker. The research in other companion animals, such as cats, is negligible, though the evidence in horses is a bit stronger than in dogs.
Stem Cell Safety
Limited evidence for efficacy almost always means limited evidence for safety as well, since we can only know the risks of a given treatment through the same robust research studies needed to show it works. As mentioned earlier, there are reports of serious adverse effects in humans from unapproved stem cell therapies. There are few such reports in companion animal patients, but it is not clear that anyone is really looking for them.
The limited clinical studies we do have, and the somewhat larger collection of lab animal studies done in dogs, suggests that the risks of stem cell therapies are low, particularly for autologous treatments.1,2 This is reassuring, but we must bear in mind the lack of targeted and long-term safety studies and the biologic complexity of stem cell therapies. There is certainly much we have yet to understand about these treatments, and it may well be that greater knowledge identifies not only more potential benefits but also unanticipated risks.
Bottom Line
Stem cell therapies have always presented a dilemma for me. On the one hand, they are based on plausible hypotheses founded in extensive basic science research. If these hypotheses prove true, then stem cells have the potential to provide dramatic health benefits to veterinary patients, including treatments for diseases we cannot currently treat safely and effectively. Who wouldn’t be excited by that!
On the other hand, stem cell therapies are a model for the backwards process of developing therapies in veterinary medicine. Insufficiently tested treatments based on very limited evidence are marketed and given to thousands of patients over many years with remarkably little oversight or incentive for manufacturers to conduct the kind of rigorous investigation we ought to have to ensure the welfare of patients. This is a dangerous way to develop novel therapies, and it can easily do harm.
I am cautiously optimistic that in the next decade we will reach the point of having several safe and effective stem cell products that have been adequately tested, and beyond that we may even be able to realize some of the more dramatic possibilities of these therapies, such as regeneration of lost nerve function or safer and more effective treatment for chronic degenerative and inflammatory diseases.
It is easy to get impatient with the progress of science. If it turns out that speculations about the potential of stem cell therapies were correct, this will likely encourage some to see shortcutting the scientific process as justifiable. I will be happy to have the treatments for my patients that stem cell therapies may offer once they are adequately validated, but I remain convinced that we need to be more patient, and more dedicated to testing such therapies thoroughly before we put them into widespread use.
References
1. Voga, M., Adamic, N., Vengust, M. & Majdic, G. Stem Cells in Veterinary Medicine—Current State and Treatment Options. Front. Vet. Sci. 7, 278 (2020).
2. MB, G., A, A. & GT, S. Mesenchymal stem cell basic research and applications in dog medicine. J. Cell. Physiol.234, (2019).
3. Lo, B. & Parham, L. Ethical issues in stem cell research. Endocr. Rev. 30, 204–13 (2009).
4. Kimura, K. et al. Efficient Reprogramming of Canine Peripheral Blood Mononuclear Cells into Induced Pluripotent Stem Cells. Stem Cells Dev. 30, 79–90 (2021).
5. Hoffman, A. M. & Dow, S. W. Concise Review: Stem Cell Trials Using Companion Animal Disease Models. doi:10.1002/stem.2377
6. Bauer, G., Elsallab, M. & Abou?El?Enein, M. Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell?Based Interventions. Stem Cells Transl. Med. 7, 676 (2018).
7. Kang, M. H. & Park, H. M. Evaluation of adverse reactions in dogs following intravenous mesenchymal stem cell transplantation. Acta Vet. Scand. 56, 16 (2014).
8. Harman, R. 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. 3, 81 (2016).
9. Black, L. L., Gaynor, J., Dean Gahring, D. & Cheryl Adams, D. Effect of Adipose-Derived Mesenchymal Stem and Regenerative Cells on Lameness in Dogs with Chronic Osteoarthritis of the Coxofemoral Joints: A Randomized, Double-Blinded, Multicenter, Controlled Trial*. Vet. Ther. 8, (2007).
10. Vilar, J. M. et al. Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs. BMC Vet. Res. 9, 131 (2013).
11. Black, L. L., Gaynor, J., Adams, C., Dhupa, S. & Sams, A. E. Effect of Intraarticular Injection of Autologous Adipose-Derived Mesenchymal Stem and Regenerative Cells on Clinical Signs of Chronic Osteoarthritis of the Elbow Joint in Dogs*. Vet. Ther. 9, (2008).
12. Shah, K. et al. Outcome of Allogeneic Adult Stem Cell Therapy in Dogs Suffering from Osteoarthritis and Other Joint Defects. Stem Cells Int. 2018, 7309201 (2018).
13. Mohoric, L., Zorko, B., Ceh, K. & Majdic, G. Blinded placebo study of bilateral osteoarthritis treatment using adipose derived mesenchymal stem cells. Slov. Vet. Res. 53, 167–74 (2016).
14. Kriston-Pál, É. et al. Characterization and therapeutic application of canine adipose mesenchymal stem cells to treat elbow osteoarthritis. Can. J. Vet. Res. 81, 73–78 (2017).
15. Cuervo, B. 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. 15, 13437–60 (2014).
16. Marx, C. et al. Acupoint injection of autologous stromal vascular fraction and allogeneic adipose-derived stem cells to treat hip dysplasia in dogs. Stem Cells Int. 2014, 391274 (2014).
