The current state of veterinary regenerative medicine

Kyla Ortved New Bolton Center, School of Veterinary Medicine, University of Pennsylvania

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 DVM, PhD, DACVS, DACVSMR

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I am delighted to serve as the guest editor for this JAVMA special supplement covering the current state of veterinary regenerative medicine. This special supplement includes an exciting combination of groundbreaking original research as well as narrative reviews on topics that highlight the broad-reaching therapeutic potential of regenerative medicine in small, large, and even exotic animals. The supplement brings to light the scope of diseases being addressed with regenerative medicine therapies, including musculoskeletal disorders, immune-mediated diseases, cancer, and neurological disorders. The advancements in regenerative medicine over the past 2 decades have been considerable, and this supplement highlights the pivotal role veterinary medicine is playing in this arena. I hope these articles are of great interest and use to you!

Small Animal

The supplement opens with a review of the clinical application of platelet-rich plasma (PRP) in canine medicine. Carr et al1 begin by highlighting the widespread use of PRP in canine medicine for many disorders, including wounds, periodontitis, joint disease, soft tissue injuries, and fractures. They offer a comprehensive review of the numerous platelet products and, importantly, consider the impact the significant variability among products has on determining clinical efficacy, including differences in platelet and WBC concentrations, as well as growth factor constituents. In the dog, PRP has been shown to improve healing of wounds and decrease pain and lameness in dogs with osteoarthritis. Additionally, several studies have shown that PRP has a positive effect on the healing of injured tendon and ligaments. This review offers important considerations and support for the clinical application of PRP in the dog.

Next, Webb et al2,3 present 2 scoping reviews of the clinical use of mesenchymal stem and stromal cell (MSC) products in cats. First, Webb et al consider the current logistics and safety surrounding MSC products,2 then present the current scope of use and efficacy.3 Like PRP therapy in the dog, MSC therapy is being applied to numerous conditions in feline medicine, including naturally occurring chronic kidney disease, refractory feline chronic gingivostomatitis, chronic enteropathy and inflammatory bowel disease, and spinal cord injuries. Fewer studies have also investigated MSCs for treatment of induced acute kidney injury, allergic asthma, and cardiomyopathy. In these 2 articles, Webb et al discuss the variability in cell source, administration routes, dose range, and the lack of a control group in most studies. Despite these significant limitations, few adverse events were reported across the studies and several studies have demonstrated therapeutic effects supporting the need for further investigation.

Keeping with a similar theme, Soltero-Rivera et al4 examine extracellular vesicles (EVs) derived from feline adipose mesenchymal stromal cells (ASCs) and placenta mesenchymal stromal cells (PMSCs). In this original research, the authors examine the morphologic and immunophenotypic differences between ASCs and PMSCs before delving into the EVs produced by each cell type. Interestingly, the authors show that the immunomodulatory mRNA and microRNA (miRNA) levels are concentrated in EVs compared to source cells, supporting the potential use of EVs in tissue regeneration. They also report on the differential miRNA expression in ASC-derived EVs compared to PMSC-EVs, which may affect their regulatory roles in anti-inflammatory and immunometabolic processes. This article is timely in its investigation of EVs, a potential biotherapeutic that has garnered significant attention not only in this supplement but across the regenerative field.

Finally, Mason5 discusses the current state of immunotherapy using genetically engineered T cells for nonmalignant diseases in the dog. This impressive narrative review not only highlights the incredible potential of cell-based immunotherapy in the dog but sheds light on the impact of translational medicine and the concept of One Health. Mason, a leader in the development of chimeric antigen receptor T-cell therapy in the dog, discusses the application of chimeric antigen in nonmalignant diseases associated with autoimmunity, fibrosis, and senescence.

Equine

The large animal manuscripts shared here continue to demonstrate the far-reaching aspects of regenerative medicine, including studies focused on MSCs, EVs, and gene therapy. First, M’Cloud et al6 provide a systematic review and meta-analysis of stem cell and PRP treatment of naturally occurring equine tendon and ligament injuries. Although the authors identified > 700 unique studies, only 21 studies met the inclusion criteria for systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Their meta-analyses showed that there was no increase in the likelihood of return to performance with biologic therapy but that administration of MSCs or a combination of MSCs and PRP significantly decreased reinjury rates. The authors also state that their results need to be interpreted cautiously due to study heterogeneity and high risk of bias in the studies. Despite these limitations, systematic reviews and meta-analyses provide high-level information for clinicians and are important additions to the literature.

Next, Koch et al7 discuss how preconditioning of equine MSCs enhances tenocyte function. The authors show that tenocytes cultured in vitro in media from MSCs that underwent “dual licensing” with IL-1β and TGF-β2 have superior migration, metabolism, and anabolic gene expression. These data support the importance of paracrine signaling in MSC therapy and provide evidence that dual-licensed MSCs may confer benefits to in vivo tendon healing. The authors also share their findings that dual licensing leads to decreased expression of major histocompatibility class–I, which may aid in the production of an allogenic MSC product that can evade the host immune system.

Pezzanite et al8 examines the transcriptomes of equine synovium collected from joints with induced staphylococcal tibiotarsal sepsis treated with immune-activated MSCs. In a previous study, the authors reported successful treatment of septic arthritis with toll-like receptor 3–activated MSCs, including reduced bacterial counts in synovial fluid and markedly improved lameness compared to antibiotic therapy alone. In this original research, the synovium collected from these septic joints was further examined to help understand the mechanisms behind the beneficial effects of MSC therapy. The authors show differential expression of 17 genes between the 2 treatment groups and use this to shed light on how MSC therapy may be modulating the innate and adaptive immune systems.

Next Connard et al9 and Gaesser et al10 explore the field of equine EVs. First, Connard et al9 show that EVs isolated from plasma and synovial fluid obtained from horses with naturally occurring post-traumatic osteoarthritis (PTOA) have altered miRNA profiles when compared to normal horses. The authors describe differentially expressed miRNAs and discuss potential downstream effects of these regulatory RNAs. This exploratory study may aid in the identification of promising biomarkers in the pathogenesis of PTOA and could facilitate the development of targeted joint therapies.

Gaesser et al10 focus their attention on developing EVs as a biotherapeutic for joint disease in the horse. In this original research, the authors describe EV production using a 3-D culture of equine bone marrow–derived MSCs. The study found that 3-D culture of MSCs on microcarrier beads did not improve overall MSC expansion but did yield more EVs produced per cell. The authors provide vital information on how culture techniques can affect EV production and offer insights into further optimization of EV production.

Goodrich et al11 demonstrate how IL-1 receptor antagonist gene therapy improves physiological, anatomical, and biological outcomes of joint degeneration in an equine model of PTOA. In this study, the authors induce PTOA using the validated “carpal chip model” followed by intra-articular treatment with an adeno-associated virus vector overexpressing IL-1 receptor antagonist. Notably, the gene therapy approach used in this study led to improved lameness scores and histological outcomes in both cartilage and subchondral bone, providing support for intra-articular gene therapy as a disease-modifying biotherapeutic.

In our second-to-last article, Colbath et al12 review the use of cellular therapy for neurological diseases of both horses and dogs. Not only is the use of cellular therapy for neurologic diseases underreported in the veterinary regenerative medicine field, but the inclusion of both equine and canine species makes this review even more intriguing. The authors highlight current research into cell therapy for neuroinflammatory and neurodegenerative diseases, among others. Despite the use of cell therapies for neurologic conditions being in its infancy, the authors state the potential for therapeutic benefit and need for future research.

Exotics

Finally, in our last manuscript, Johnson13 reviews the applications of MSCs in exotic animal species. Johnson has been involved in the treatment of many exotic animal species with MSC therapy and in this review describes the current state of cell-based therapies, need for novel therapies in animals that often cannot be treated repeatedly, and potential for therapeutic benefit in the treatment of joint and soft tissue disorders, as well as autoimmune, inflammatory, and infectious diseases.

Sincerely,

Kyla Ortved DVM, PhD, DACVS, DACVSMR

New Bolton Center, School of Veterinary Medicine, University of Pennsylvania

References

  • 1.

    Carr BJ, Miller AV, Colbath AC, Peralta S, Frye CW. Literature review details and supports the application of platelet-rich plasma products in canine medicine, particularly as an orthobiologic agent for osteoarthritis. J Am Vet Med Assoc. 2024;262(suppl 1):S8S15. doi:10.2460/javma.23.12.0692

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  • 2.

    Webb TL, Webb CB. Scoping review of the use of mesenchymal stem and stromal cell products in cats, Part 1: current logistics and safety. J Am Vet Med Assoc. 2024;262(suppl 1):S16S23. doi:10.2460/javma.24.02.0074

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  • 3.

    Webb TL, Webb CB. Scoping review of the use of mesenchymal stem and stromal cell products in cats, Part 2: current scope and efficacy. J Am Vet Med Assoc. 2024;262(suppl 1):S24S30. doi:10.2460/javma.24.02.0080

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  • 4.

    Soltero-Rivera M, Arzi B, Bourebaba L, Marycz K. Distinctive characteristics of extracellular vesicles from feline adipose and placenta stromal cells unveil potential for regenerative medicine in cats. J Am Vet Med Assoc. 2024;262(suppl 1):S31S39. doi:10.2460/javma.23.11.0662

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  • 5.

    Mason NJ. Immunotherapy with genetically engineered T cells holds promise for the treatment of nonmalignant diseases in the dog. J Am Vet Med Assoc. 2024;262(suppl 1):S40S49. doi:10.2460/javma.24.02.0113

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  • 6.

    M’Cloud WRC, Guzmán KE, Panek CL, Colbath AC. Stem cells and platelet-rich plasma for the treatment of naturally occurring equine tendon and ligament injuries: a systematic review and meta-analysis. J Am Vet Med Assoc. 2024;262(suppl 1):S50S60. doi:10.2460/javma.23.12.0723

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  • 7.

    Koch DW, Froneberger A, Berglund A, Connard S, Souther A, Schnabel LV. IL-1β + TGF-β2 dual-licensed mesenchymal stem cells have reduced major histocompatibility class I expression and positively modulate tenocyte migration, metabolism, and gene expression. J Am Vet Med Assoc. 2024;262(suppl 1):S61S72. doi:10.2460/javma.23.12.0708

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  • 8.

    Pezzanite LM, Chow L, Engiles JB, et al. Targeted transcriptomic analysis of synovial tissues from horses with septic arthritis treated with immune-activated mesenchymal stromal cells reveals induction of T-cell response pathways. J Am Vet Med Assoc. 2024;262(suppl 1):S73S82. doi:10.2460/javma.23.10.0561

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  • 9.

    Connard SS, Gaesser AM, Clarke EJ, et al. Plasma and synovial fluid extracellular vesicles display altered microRNA profiles in horses with naturally occurring post-traumatic osteoarthritis: an exploratory study. J Am Vet Med Assoc. 2024;262(suppl 1):S83S96. doi:10.2460/javma.24.02.0102

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  • 10.

    Gaesser AM, Usimaki AIJ, Barot DA, et al. Equine mesenchymal stem cell–derived extracellular vesicle productivity but not overall yield is improved via 3-D culture with chemically defined media. J Am Vet Med Assoc. 2024;262(suppl 1):S97S108. doi:10.2460/javma.24.01.0001

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  • 11.

    Goodrich LR, McIlwraith CW, Grieger J, et al. IL-1ra gene therapy in equine osteoarthritis improves physiological, anatomical, and biological outcomes of joint degeneration. J Am Vet Med Assoc. 2024;262(suppl 1):S109S120. doi:10.2460/javma.24.02.0078

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  • 12.

    Colbath AC, Goodrich L, Frye C, Dow S. Review of cellular therapies provides new insights into the potential treatment of diverse neurologic diseases in horses and dogs. J Am Vet Med Assoc. 2024;262(suppl 1):S121S130. doi:10.2460/javma.23.12.0709

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  • 13.

    Johnson VA. Review of current and potential applications of mesenchymal stem cells in exotic animal species. J Am Vet Med Assoc. 2024;262(suppl 1):S131S140. doi:10.2460/javma.24.01.0034

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