Available articles

PUBMED search terms included ((feline) AND ((stem cell) OR (stromal cell) OR (stromal vascular fraction))), which resulted in 1,664 articles. A filter was applied to limit dates from 2002 to 2024 based on the date of the first publication describing feline MSCs.² Articles were individually reviewed for relevance as described in a previous article.¹

Twenty-six articles were identified that described primary administration of MSCs or MSC products to cats in experimental and clinical studies. Of these 26 publications, 2 studies were in healthy cats and excluded from this review. Fourteen of the 24 (58.3%) publications^3–16 were studies in cats with naturally occurring disease, 8 (8/24 [33.3%])^17–24 were studies in induced models of disease, and 2 were single case studies^25–26 for a total of 192 treated cats. One retrospective study²⁷ reported on long-term follow-up on some of the cats included in the previous 24 articles; this study was not included in the results due to overlap with previous articles.

Eleven of the 24 (45.8%) publications^{5,6,12,15,17-21,23,24} describing primary administration of MSCs or MSC products to cats with disease included a control group (Figure 1). The number of cats treated per publication ranged from 1 to 24, with a median of 5 cats. Cats were treated with a median of 2 doses (range, 1 to 6). The majority of cats were treated with allogeneic cells (117/168 [69.6%] cats; Figure 2); information on donor type was not available for 1 study,¹⁹ accounting for 24 cats. The majority of MSC products were delivered IV (136/192 [70.8%] cats). The overall rate of adverse events, defined as any untoward medical occurrence associated with the use of a drug whether or not considered drug-related, was up to 22.4% (43/192 cats) as inferred from the publications; in studies that did not state the number of cats that experienced adverse events, the adverse events were counted as occurring individually. Up to 18 cats with naturally occurring disease (18/112 [16.1%] cats) and 25 cats with induced disease (25/80 [31.3%] cats) had reported adverse events.

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Total publications describing administration of mesenchymal stem and stromal cell products to cats by disease and whether the study had a control group (enteropathy includes chronic enteropathy and inflammatory bowel disease studies). AKI = Acute kidney injury. CKD = Chronic kidney disease. FCGS = Feline chronic gingivostomatitis.

Citation: Journal of the American Veterinary Medical Association 262, S1; 10.2460/javma.24.02.0080

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Number of cats treated with mesenchymal stem and stromal cell products by disease and donor cell type (enteropathy includes chronic enteropathy and inflammatory bowel disease studies). AKI = Acute kidney injury. CKD = Chronic kidney disease. FCGS = Feline chronic gingivostomatitis.

Citation: Journal of the American Veterinary Medical Association 262, S1; 10.2460/javma.24.02.0080

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Diseases

Cats with 12 different diseases were treated with MSCs or MSC products in the reviewed publications (Figure 3). Six of the diseases were naturally occurring including 112 of the 192 (58.3%) treated cats, and 6 of the diseases were induced including 80 of the 192 (41.7%) treated cats. Naturally occurring chronic kidney disease (CKD) and refractory feline chronic gingivostomatitis (FCGS) were the focus of the majority of publications (5 each; Figure 1) and also included the most cats treated, with 41 (21.4%) and 45 (23.4%) of the 192 treated cats, respectively. Two related publications^5,15 evaluated the use of MSCs in naturally occurring chronic enteropathy (10/192 [5.2%] treated cats) and inflammatory bowel disease (IBD; 6/192 [3.1%]). One publication each evaluated MSC use in naturally occurring eosinophilic keratitis (5/192 [2.6%] treated cats)¹⁰ and chronic spinal cord injury (3/192 [1.6%]).¹⁴ The 2 case reports evaluated MSC use with implants in a large osseous defect in the tarsus²⁶ and a chronic oronasal defect.²⁵

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Number of cats treated with mesenchymal stem and stromal cell products by disease and disease category (enteropathy includes chronic enteropathy and inflammatory bowel disease studies). AKI = Acute kidney injury. CKD = Chronic kidney disease. FCGS = Feline chronic gingivostomatitis.

Citation: Journal of the American Veterinary Medical Association 262, S1; 10.2460/javma.24.02.0080

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Studies involving induced disease in cats included 2 each on models of acute kidney injury (AKI; 13/192 [6.8%] treated cats)^21,23 and allergic asthma (9/192 [4.7%]).^17,20 Additional single studies evaluated induced CKD (18/192 [9.4%] treated cats),²² multiple sclerosis (MS; 5/192 [2.6%]),²⁴ cardiomyopathy (11/192 [5.7%]),¹⁸ and traumatic optic neuropathy (24/192 [12.5%]).¹⁹

Outcomes

CKD—Six studies evaluated MSC products in CKD, 5 of them in naturally occurring disease^3,4,6,8,11 and 1 in an induced model of disease²² treating a total of 59 cats. These studies used a variety of donor types, cell sources, dosages, and administration routes, and adverse events were reported in up to 25 of the 59 (42.4%) treated cats. The first study³ showed mild improvement in creatinine and glomerular filtration rate after single intrarenal injections of autologous bone marrow–derived or adipose-derived MSCs over the 8-week follow-up period. Two additional studies^4,8 showed mild improvement in creatinine in some cats after 3 IV injections of allogeneic adipose-derived MSCs and 2 IV injections of amniotic membrane-derived MSCs. Two studies^6,11 showed no improvement or variable results over the 2- and 3-month study periods after 3 IV injections of allogeneic adipose-derived MSCs or 2 intra-arterial injections of autologous adipose-derived stromal vascular fraction (SVF), including the only randomized, placebo-controlled study in CKD to date. The most recent study²² in cats with induced CKD showed at least 20% increased glomerular filtration rate in 50% of the cats treated with 2 IV injections of allogeneic uterine-derived MSCs as well as increased water and diet consumption over the 6-month study period.

AKI—Two randomized, controlled studies inves­tigated the use of MSCs in induced models of AKI.^21,23 The first evaluated single IV injections of 4 X 10⁶ allogeneic adipose-derived (5 cats) and bone marrow–derived (5 cats) MSCs.²¹ Cats were followed for 6 days, and no response to therapy was noted. Adverse events were reported in 7 of the 10 (70%) cats. The second study used extracellular vesicles excreted from allogeneic adipose-derived MSCs administered once IV to treat postrenal AKI induced through urethral obstruction in 3 cats.²³ The cats were only monitored for 3 days, and no adverse events were reported. Results showed that EV administration was associated with a faster return to normal levels of creatinine and BUN.

FCGS—Five studies^7,9,12,13,16 investigated the use of MSC products in 45 cats with FCGS. Adverse events were reported in 10 of the 45 (22.2%) treated cats. The first 4 studies^7,9,12,13 used autologous or allogeneic MSCs and the same protocol (2 IV doses given 30 days apart), cell type (adipose-derived, recultured), and dosage (20 X 10⁶ cells) in cases of refractory FCGS. The 32 cats treated in the first 3 studies^7,9,12 showed a 57% to 72% response rate out to 20 months, with higher response rates seen with autologous cells. One of these studies¹² was a randomized, controlled, cross-over trial, and no improvement was seen in the control cats during the 3- to 6-month monitoring period. The fourth study¹³ evaluated MSCs in FCGS before full-mouth tooth extractions and saw no clinical efficacy. The most recent study¹⁶ used one 10 X 10⁶ IV dose of cryopreserved, allogeneic placenta-derived MSCs in 8 cats with refractory FCGS and saw 27% to 86% clinical improvement in the stomatitis disease activity index scores in all cats.

Chronic enteropathy and IBD—Two randomized, controlled studies^5,15 on chronic enteropathy and IBD were performed by the same laboratory in sequence, and no adverse events were noted. The initial single-blinded, placebo-controlled study⁵ treated 10 cats with chronic enteropathy with 2 IV doses of fresh, allogeneic adipose-derived MSCs, and 88.9% of cats showed clinical improvement. The second study¹⁵ used the same protocol in 6 cats with IBD compared to 6 cats receiving standard of care (ie, prednisone). Clinical outcome in the 6 treated cats was comparable to prednisone with improved feline chronic enteropathy activity index scores only seen in the MSC-treated group.

Eosinophilic keratitis—A single study¹⁰ evalu­ated the use of 2 subconjunctival injections of 2 X 10⁶ allogeneic cryopreserved adipose-derived MSCs given 60 days apart in 5 cats with refractory eosinophilic keratitis. The cats were followed for 11 months, and no adverse events were reported. There was no control group. All cats showed complete remission of clinical signs at 6 months, which remained stable until the last follow-up.

Chronic spinal cord injury—A single study¹⁴ evaluated the use of a combined intrathecal and IV injection of autologous, uncultured bone marrow mononuclear cells and platelet-rich plasma in 3 cats with chronic spinal cord injury refractory to standard treatment and rehabilitation for at least 2 months. The cats were followed for 90 days, and no adverse events were reported. There was no control group. The authors¹⁴ reported that treatment combined with physical rehabilitation led to restoration of weight-bearing locomotor function and spinal reflexes, although these improvements diminished after 45 days.

Osseous defects—Two independent case studies^25,26 reported on the use of MSCs and bone marrow on implants used to treat osseous defects. The first case used autologous platelet-rich plasma and uncultured bone marrow applied to a 3-D–printed polycaprolactone scaffold for treatment of a chronic oronasal defect.²⁵ Although the implant was not observed and limited bone healing was noted on CT scan 2.5 months postoperatively, the cat was followed for 10 months with no adverse events, and good wound healing and improved quality of life were reported. The second case study²⁶ described the treatment of an infected large osseous defect in a feline tarsus and used 5 X 10⁶ early passage autologous, adipose-derived MSCs treated with osteoblast conditioned media impregnated onto 3-D–printed trabecular metal spacer. The cat was followed for 18 months with no adverse events reported related to the MSCs although some complications with the surgical site were described secondary to self-trauma. Evidence of bone growth and implant integration was present at 6 months postimplant.

Allergic asthma—Two randomized, controlled studies^17,20 investigated MSCs in an induced model of feline allergic asthma. Allogeneic adipose-derived MSCs were shipped to the study site and included both cryopreserved and freshly cultured cells in a range of doses given IV 6 times in the initial study and 5 times in the second study. In the first study,¹⁷ 5 cats were followed for 12 months and no decrease in airway inflammation was observed; however, MSC treatment temporarily decreased airway remodeling as measured using CT-derived inspiratory global bronchial wall thickness and global lung attenuation scores. The 4 cats in the second study²⁰ were followed for 9 months and showed possible delayed reduction in airway inflammation, hyperresponsiveness, and remodeling. The only reported adverse event was the development of a scrotal sarcoma in 1 cat 1 month poststudy.

Multiple sclerosis—A single study²⁴ evaluated the effects of a single intrathecal injection of 10 X 10⁶ laser-activated, fresh nucleated cells in SVF from autologous adipose tissue in 5 cats with induced multiple sclerosis. The study was placebo controlled, and the cats were followed for 28 days. Adverse events were not reported. SVF treatment resulted in improved locomotion, remyelination, and regeneration capacity, decreased lesion extent and intensity, and reduced apoptosis and axonal regeneration.

Cardiomyopathy—A single study¹⁸ evaluated the therapeutic benefit of a single intracoronary injection of 1 X 10⁶ autologous CD117+ isolated cardiac-derived stem cells in 7 cats and bone marrow–derived MSCs in 4 cats after injury in isoproterenol-induced cardiomyopathy. The study was placebo-controlled, and the cats were followed for 66 days with no reported adverse events. Although both cell types improved cardiac function and attenuated pathological remodeling, MSCs appeared to confer additional benefits, and the authors concluded that MSCs may be the optimal source of stem cells to treat cardiac disease.

Traumatic optic neuropathy—A single study¹⁹ evaluated whether intravitreal injection of bone marrow–derived MSCs could increase survival of retinal ganglion cells after induced traumatic optic neuropathy in 24 cats. The study was placebo controlled, and the cats were followed for 28 days with no reported adverse events. MSC transplantation was found to slow apoptosis of retinal ganglion cells and thereby mediate neuroprotection after optic nerve injury potentially mediated by secretion of brain-derived neurotrophic factor.

Are MSCs or MSC products effective to treat disease?

Current literature supports that MSCs and MSC products show promise in treating certain cats and diseases. However, the level of evidence for most diseases is very low due to low numbers of studies, small patient numbers, and lack of randomized, controlled trials. The most commonly studied diseases for application of MSC-based therapies in cats are CKD and refractory FCGS, and only 1 controlled clinical trial has been performed in a small number of cats with each disease.^6,12 Both of these diseases lack effective therapies for a large number of affected cats. Overall, CKD is the disease with the most cats treated with MSCs thus far, with 59 cats over 6 studies (Figure 3). However, the wide variety of protocols, applications, and monitoring over a small number of cats make comparisons even within 1 disease challenging. Outcomes for CKD cats treated with MSCs have generally been less than desired, with some studies showing no benefit at all, including the controlled trial, and others showing modest improvement in some parameters. An important question is whether significant changes in values such as creatinine are clinically relevant to patient outcomes. Although no impact on mortality in CKD cats has been demonstrated, improvement in behavior has been reported.^11,22

The most comparative data for MSC use in cats is available for refractory FCGS where many of the studies have been performed using the same protocol in the 45 treated cats summarized in the reviewed publications. The current available studies of cats with refractory FCGS treated with MSCs have shown marked improvement or complete, durable cure in the majority of cats, especially with autologous therapy. A recent retrospective study²⁷ reported an overall positive response rate of 65.5%, with 58.6% of cats exhibiting long-lasting improvement or cure. Importantly, 91% of owners reported they would seek treatment with MSC again.²⁷ Interestingly, a more recent clinical trial¹³ evaluated adipose-derived MSC in cats with FCGS before full-mouth tooth extractions and showed a lack of clinical efficacy. Some of the studies^7,12,27 showed that clinical responses were correlated with potential biomarkers of disease severity including levels of CD8+ lymphocytes and cytokines, such as IL-6, IL-1β, and interferon-γ, among others. Although outside current normal clinical diagnostics, these findings provide information on MSC mechanism of action and a means of identifying cats that might respond to MSC therapy.³²

The remaining diseases studied have very little currently available data to determine potential efficacy and many involved induced disease as preclinical studies for people. The 2 most promising, however, are feline enteropathy and refractory eosinophilic keratitis. Two studies^5,15 are available treating cats for chronic enteropathy or IBD, both of which were blinded, randomized controlled trials. The first study⁵ was placebo controlled and showed improved clinical signs in 8 of 9 treated cats (1 of the 10 cats was lost to follow-up) with no reported adverse events. The follow-up study¹⁵ in cats with diagnosed IBD directly compared MSC therapy with standard-of-care treatment. Although the groups were small (6 cats each), similar improvement was seen in both groups with significantly improved feline chronic enteropathy activity index scores only in the MSC-treated group. Again, no adverse events were seen in MSC-treated cats.

The 1 study¹⁰ using allogeneic adipose-derived MSC subconjunctivally in 5 cats with refractory feline eosinophilic keratitis showed a 100% response rate by 6 months with no reported adverse events. Unfortunately, no follow-up studies have been published thus far. Several studies^{9,10,17,20,27} have similarly noted that response to MSC therapies in cats may take 6 months or longer to fully appear. Considering the median follow-up time in the current studies was 4.5 months, longer follow-up times should be considered in future investigations.

What MSC or MSC product is most effective?

With the small number of currently available studies and the large variability in study protocols, the most promising MSC or MSC product is not currently evident. Some potential differences in efficacy have been noted, such as an increased response rate in cats with refractory FCGS when autologous cells are used.²⁷ However, the response rate has to be balanced with twice the incidence of adverse events, such as increased respiratory rate, fever, vomiting, and lethargy, even if mostly mild and transient.²⁷ Autologous cells may carry less risk of infectious disease transfer but may have altered growth characteristics or function due to the presence of disease and the impact of concurrent medication administration.^3,33,34 Additionally, the procedures required to collect tissues from sick cats may detract from any perceived benefit of using autologous cells.^3,11

Few clinical studies have directly compared different cell types, doses, or administration characteristics in vivo. In 1 of the CKD studies,⁴ increased adverse events were seen with higher doses of cells taken directly from cryopreservation. Intrarenal or intra-arterial administration routes are more labor intensive and technically demanding than IV delivery.^3,11 In FCGS, a recent study¹⁶ evaluated the use of placenta-derived MSCs as an alternative to adipose-derived MSCs and saw clinical improvement in all cats. Baring identification of significant differences in safety or outcome, the most easily available and resource-sparing options for MSC product generation and administration decrease donor, recipient, and care-giver burden as well cost of treatment, which can be significant in cell-based therapies. Continued in vitro studies evaluating cell characteristics, culture conditions, and mechanism of action can help identify the most promising treatment options and recipients before in vivo studies are performed.

Next steps

Combined with the increasing number of publications about feline MSC cell characterization and mechanism of action,¹ the studies reviewed in this article provide valuable information to direct and optimize further clinical studies using MSC products in cats. As an example, IBD, kidney disease, and FCGS are currently listed as areas of interest or clinical trials by companies involved in veterinary regenerative medicine suggesting these applications are the most promising for product development. Recent conference proceedings related to the use of MSCs in cats also suggest additional ongoing clinical trials in refractory FCGS³⁵ and feline infectious peritonitis for lymphoid tissue regeneration and effective antiviral immunity.³⁶

This 2-part review provides current information on the use of MSC products in cats. Combined with knowledge of the current policies and regulations on the use of these products in client-owned animals,^{28,29,37–40} veterinary clinicians can use this information to help make informed recommendations to owners about the participation of their cats in clinical trials using MSC products. Additional information and open clinical trials can be found by contacting researchers in the field and searching the AVMA’s Veterinary Clinical Trials Registry⁴¹ and the FDA Center for Veterinary Medicine Clinical Field Studies for Animal Cells, Tissues, and Cell- and Tissue-Based Products webpage.⁴² Informed, collaborative efforts between clinicians, researchers, regulators, and pet owners provide the best opportunity to design and complete quality, high-powered veterinary clinical trials that translate potential clinical solutions, such as MSC products, safely and effectively from the laboratory to the patient to address unmet therapeutic needs and improve health outcomes.

In conclusion, currently, 24 publications are available that summarize the treatment of 192 cats with 12 naturally occurring and induced diseases using MSC products. Treatment outcomes have ranged from no response to long-term cure, depending on the disease being treated and the particular study. Some of these early studies show promise and provide significant information to direct both the design and focus of larger clinical trials investigating the safety and efficacy of MSCs and MSC products for veterinary and human applications.