Single and repeated intra-articular injections in the tarsocrural joint with allogeneic and autologous equine bone marrow-derived mesenchymal stem cells are safe, but did not reduce acute inflammation in an experimental interleukin-1β model of synovitis.
Abstract: Allogeneic and autologous bone marrow-derived mesenchymal stem cells (BMDMSCs) have been administered in equine joints for their anti-inflammatory effects. However, allogeneic BMDMSC offer multiple clinical and practical advantages. Therefore, it is important to determine the relative effectiveness of allogeneic vs autologous BMDMSCs. Objective: The objective of the study was to compare the inflamed joint response to autologous vs allogeneic BMDMSCs injections, and to determine if either treatment generated an anti-inflammatory effect. Methods: Randomised controlled study. Methods: Bone marrow was harvested from eight horses. Autologous BMDMSCs and pooled allogeneic BMDMSCs were culture expanded, cryopreserved and thawed immediately prior to administration. Ten million autologous BMDMSCs were administered with 75 ng rIL-1β into one tarsocrural joint and the contralateral tarsocrural joint received allogeneic BMDMSC plus 75 ng rIL-1β. Repeat injections were performed with the same treatment administered into the same joint. Four additional horses received 75 ng rIL-1β alone in a single tarsocrural joint. Clinical parameters (lameness, joint circumference and joint effusion) and synovial fluid parameters, including nucleated cell count (NCC), differential cell count, total protein (TP), prostaglandin E2 (PGE2 ) and C-reactive protein (CRP), were measured at baseline, 6, 12, 24, 72, 168 and 336 hours post-injection. Results: No difference was detected between autologous and allogeneic treatment groups with respect to subjective lameness, joint effusion, joint circumference, NCC, TP, differential cell count, CRP or PGE2 . Neither autologous nor allogeneic treatments resulted in an improvement in clinical or cytological parameters over that elicited by rIL-1β alone. Conclusions: A single dose of rIL-1β was evaluated and resulted in a severe synovitis which may have been too severe to observe a BMDMSC-mediated effect. Conclusions: This study revealed that allogeneic and autologous BMDMSCs resulted in an equivalent clinical and cytological response. Allogeneic and autologous BMDMSCs were equally ineffective in reducing the inflammatory response from acute rIL-1β-induced joint inflammation in horses.
© 2019 EVJ Ltd.
Publication Date: 2020-02-14 PubMed ID: 31821594PubMed Central: PMC7283005DOI: 10.1111/evj.13222Google Scholar: Lookup
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- Journal Article
- Randomized Controlled Trial
- Veterinary
Summary
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The research study investigated the impact of autologous and allogeneic bone marrow-derived mesenchymal stem cells (BMDMSCs) on inflammation within the joints of horses, finding that neither type of BMDMSC offered an anti-inflammatory effect in an experimental model of severe synovitis.
Objective and Methodology
The researchers aimed to compare the response of inflamed equine joints to both autologous (stem cells from the same individual) and allogeneic (stem cells from a different individual) BMDMSCs, with the goal of determining if either form of treatment yielded an anti-inflammatory effect.
- Bone marrow was collected from eight horses, with both autologous and pooled allogeneic BMDMSCs being cultivated, frozen, and then thawed immediately before being used.
- Each horse had one joint treated with autologous BMDMSCs combined with 75 ng rIL-1β (a pro-inflammatory cytokine); the other joint was treated with allogeneic BMDMSCs and the same dose of rIL-1β.
- The process was then replicated, with the same treatments being given to the same joints. Four additional horses were given 75 ng rIL-1β alone to serve as controls.
Parameters and Measurements
Numerous clinical and synovial fluid parameters were monitored and measured at a series of time points after injection, including:
- Level of lameness
- Joint size and joint fluid quantity
- Synovial fluid elements, such as nucleated cell count (NCC), differential cell count, total protein (TP), prostaglandin E (PGE) and C-reactive proteins (CRP)
Results of the Study
The results suggested that there was no significant difference between the autologous and allogeneic treatment groups in terms of lameness, joint swelling, synovial fluid measures or cytological parameters. Notably, neither the autologous nor allogeneic treatments resulted in an improvement greater than that evoked by rIL-1β on its own.
Conclusions
The research found that a single dose of rIL-1β led to severe synovitis, a condition possibly too intense for any potential BMDMSC-mediated impact to be discernible. The findings showed that both types of BMDMSC treatment had equivalent clinical and cytological outcomes, which unfortunately were ineffective in reducing the inflammation caused by acute rIL-1β-triggered joint inflammation in the horses. As such, further research is needed to determine the potential therapeutic value of BMDMSCs in managing joint inflammation.
Cite This Article
APA
Colbath AC, Dow SW, Hopkins LS, Phillips JN, McIlwraith CW, Goodrich LR.
(2020).
Single and repeated intra-articular injections in the tarsocrural joint with allogeneic and autologous equine bone marrow-derived mesenchymal stem cells are safe, but did not reduce acute inflammation in an experimental interleukin-1β model of synovitis.
Equine Vet J, 52(4), 601-612.
https://doi.org/10.1111/evj.13222 Publication
Researcher Affiliations
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA.
- Center for Immune and Regenerative Medicine, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado, USA.
- Department of Clinical Sciences, College of Veterinary Medicine, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado, USA.
- Orthopedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado, USA.
- Orthopedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado, USA.
- Orthopedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado, USA.
MeSH Terms
- Animals
- Bone Marrow
- Hematopoietic Stem Cell Transplantation / veterinary
- Horse Diseases
- Horses
- Inflammation / veterinary
- Injections, Intra-Articular / veterinary
- Interleukin-1beta
- Mesenchymal Stem Cell Transplantation / veterinary
- Mesenchymal Stem Cells
- Synovial Fluid
- Synovitis / veterinary
Grant Funding
- T32 OD010437 / NIH HHS
- NIH, National Research Service Award
- Grayson-Jockey Club Research Foundation
- Wayne and Nancy McIlwraith Fellowship
Conflict of Interest Statement
Authors’ declaration of interests. No competing interests have been declared.
References
This article includes 48 references
- Broeckx S, Suls M, Beerts C, Vandenberghe A, Seys B, Wuertz-Kozak K, Duchateau L, Spaas JH. Allogenic mesenchymal stem cells as a treatment for equine degenerative joint disease: a pilot study.. Curr Stem Cell Res Ther 9, 497–503.
- Broeckx S, Zimmerman M, Crocetti S, Suls M, Marien T, Ferguson SJ, Chiers K, Duchateau L, Franco-Obregon A, Wuertz K, Spaas JH. Regenerative therapies for equine degenerative joint disease: a preliminary study.. PLoS One 9, e85917.
- Van Loon VJ, Scheffer CJ, Genn HJ, Hoogendoorn 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 34, 92–97.
- Ferris DJ, Frisbie DD, Kisiday JD, McIlwraith CW, Hague BA, Major MD, Schneider RK, Zubrod CJ, Kawcak CE, Goodrich LR. Clinical outcome after intra-articular administration of bone marrow derived mesenchymal stem cells in 33 horses with stifle injury.. Vet Surg 43, 255–265.
- Smith RK, Werling NJ, Dakin SG, Alam R, Goodship AE, Dudhia J. Beneficial effects of autologous bone marrow-derived mesenchymal stem cells in naturally occurring tendinopathy.. PLoS One 8, e75697.
- Frisbie DD, Kisiday JD, Kawcak CE, Werpy NM, McIlwraith CW. Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis.. J Orthop Res 27, 1675–1680.
- Colbath AC, Dow SW, Phillips JN, McIlwraith CW, Goodrich LR. Autologous and Allogeneic Equine Mesenchymal Stem Cells Exhibit Equivalent Immunomodulatory Properties In Vitro.. Stem Cells Dev 26, 503–511.
- Ranera B, Antczak D, Miller D, Doroshenkova T, Ryan A, McIlwraith CW, Barry F. Donor-derived equine mesenchymal stem cells suppress proliferation of mismatched lymphocytes.. Equine Vet J 48, 253–260.
- Hussein MR, Fathi NA, El-Din AM, Hassan HI, Abdullah F, Al-Hakeem E, Backer EA. Alterations of the CD4(+), CD8 (+) T cell subsets, interleukins-1beta, IL-10, IL-17, tumor necrosis factor-alpha and soluble intercellular adhesion molecule-1 in rheumatoid arthritis and osteoarthritis: preliminary observations.. Pathol Oncol Res 14, 321–328.
- Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis.. J Rheumatol 24, 365–371.
- Elsaid KA, Ubhe A, Shaman Z, D’Souza G. Intra-articular interleukin-1 receptor antagonist (IL1-ra) microspheres for posttraumatic osteoarthritis: in vitro biological activity and in vivo disease modifying effect.. J Exp Orthop 3, 18.
- Frisbie DD, Ghivizzani SC, Robbins PD, Evans CH, McIlwraith CW. Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene.. Gene Ther 9, 12–20.
- Pigott JH, Ishihara A, Wellman ML, Russell DS, Bertone AL. Investigation of the immune response to autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses.. Vet Immunol Immunopathol 156, 99–106.
- Joswig AJ, Mitchell A, Cummings KJ, Levine GJ, Gregory CA, Smith R 3rd, Watts AE. Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model.. Stem Cell Res Ther 8, 42.
- Colbath AC, Dow SW, Hopkins LS, Phillips JN, McIlwraith CW, Goodrich LR. Allogeneic vs. autologous intra-articular mesenchymal stem cell injection within normal horses: Clinical and cytological comparisons suggest safety.. Equine Vet J .
- Broeckx S, Spaas JH, Chiers K, Duchateau L, Van Hecke L, Van Brantegem L, Dumoulin M, Martens AM, Pille F. Equine allogeneic chondrogenic induced mesenchymal stem cells: a GCP target animal safety and biodistribution. Res Vet Sci 117, 246–254.
- Williams LB, Koenig JB, Black B, Gibson TW, Sharif S, Koch TG. Equine allogeneic umbilical cord blood derived mesenchymal stromal cells reduce synovial fluid nucleated cell count and induce mild self-limiting inflammation when evaluated in an lipopolysaccharide induced synovitis model.. Equine Vet J 48, 619–625.
- Ardanaz N, Vazquez FJ, Romero A, Remacha AR, Barrachina L, Sanz A, Ranera B, Vitoria A, Albareda J, Prades M, Zaragoza P, Martin-Burriel I, Rodellar C. Inflammatory response to the administration of mesenchymal stem cells in an equine experimental model: effect of autologous, and single and repeat doses of pooled allogeneic cells in healthy joints.. BMC Vet Res 12, 65.
- Berglund AK, Schnabel LV. Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies.. Equine Vet J 49, 539–544.
- Colbath AC, Dow SW, Hopkins LS, Phillips JN, McIlwraith CW, Goodrich LR. Induction of synovitis using interleukin-1 beta: are there differences in the response of middle carpal joint compared to the tibiotarsal joint.. Front Vet Sci .
- . AAEP Lameness Exams: Evaluating the Lame Horse.. .
- Ross TN, Kisiday JD, Hess T, McIlwraith CW. Evaluation of the inflammatory response in experimentally induced synovitis in the horse: a comparison of recombinant equine interleukin 1 beta and lipopolysaccharide.. Osteoarthritis Cartilage 20, 1583–1590.
- Mokbel AN, El Tookhy OS, Shamaa AA, Rashed LA, Sabry D, El Sayed AM. Homing and reparative effect of intra-articular injection of autologus mesenchymal stem cells in osteoarthritic animal model.. BMC Musculoskelet Disord 12, 259.
- Textor JA, Willits NH, Tablin F. Synovial fluid growth factor and cytokine concentrations after intra-articular injection of a platelet-rich product in horses.. Vet J 198, 217–223.
- Carter-Arnold JL, Neilsen NL, Amelse LL, Odoi A, Dhar MS. In vitro analysis of equine, bone marrow-derived mesenchymal stem cells demonstrates differences within age- and gender-matched horses.. Equine Vet J 46, 589–595.
- Choudhery MS, Khan M, Mahmood R, Mehmood A, Khan SN, Riazuddin S. Bone marrow derived mesenchymal stem cells from aged mice have reduced wound healing, angiogenesis, proliferation and anti-apoptosis capabilities.. Cell Biol Int 36, 747–753.
- Kol A, Wood JA, Carrade Holt DD, Gillette JA, Bohannon-Worsley LK, Puchalski SM, Walker NJ, Clark KC, Watson JL, Borjesson DL. Multiple intravenous injections of allogeneic equine mesenchymal stem cells do not induce a systemic inflammatory response but do alter lymphocyte subsets in healthy horses.. Stem Cell Res Ther 6, 73.
- Broeckx S, Borena BM, Zimmerman M, Marien T, Seys B, Suls M, Duchateau L, Spaas JH. Intravenous application of allogenic peripheral blood-derived mesenchymal stem cells: a safety assessment in 291 equine recipients.. Curr Stem Cell Res Ther 9, 452–457.
- Marinas-Pardo L, Garcia-Castro J, Rodriguez-Hurtado I, Rodriguez-Garcia MI, Nunez-Naveira L, Hermida-Prieto M. Allogeneic adipose-derived mesenchymal stem cells (Horse Allo 20) for the treatment of osteoarthritis associated lameness in horses: characterization, safety and efficacy of intraarticular treatment.. Stem Cells Dev 27, 1147–1160.
- Carmalt JL, Bell CD, Tatarniuk DM, Suri SS, Singh B, Waldner C. Comparison of the response to experimentally induced short-term inflammation in the temporomandibular and metacarpophalangeal joints of horses.. Am J Vet Res 72, 1586–1591.
- Cassano JM, Schnabel LV, Goodale MB, Fortier LA. Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment.. Stem Cell Res Ther 9, 82.
- Cassano JM, Schnabel LV, Goodale MB, Fortier LA. The immunomodulatory function of equine MSCs is enhanced by priming through an inflammatory microenvironment or TLR3 ligand.. Vet Immunol Immunopathol 195, 33–39.
- Vezina Audette R, Lavoie-Lamoureux A, Lavoie JP, Laverty S. Inflammatory stimuli differentially modulate the transcription of paracrine signaling molecules of equine bone marrow multipotent mesenchymal stromal cells.. Osteoarthritis Cartilage 21, 1116–1124.
- Nelson BB, King MR, Frisbie DD. Assessment of a novel equine tarsocrural experimental joint disease model using recombinant interleukin-1beta and arthroscopic articular sampling of the medial malleolus of the tibia on the standing sedated horse.. Vet J 229, 54–59.
- Ross-Jones TN, McIlwraith CW, Kisiday JD, Hess TM, Hansen DK, Black J. Influence of an n-3 long-chain polyunsaturated fatty acid-enriched diet on experimentally induced synovitis in horses.. J Anim Physiol Anim Nutr (Berl) 100, 565–577.
- Guo YL. The underdeveloped innate immunity in embryonic stem cells: The molecular basis and biological perspectives from early embryogenesis.. Am J Reprod Immunol e13089.
- Ha CW, Park YB, Kim SH, Lee HJ. Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair.. Arthroscopy 35, 277–288 e272.
- Duan W, Lopez MJ. Effects of Cryopreservation on Canine Multipotent Stromal Cells from Subcutaneous and Infrapatellar Adipose Tissue.. Stem Cell Rev 12, 257–268.
- James AW, Levi B, Nelson ER, Peng M, Commons GW, Lee M, Wu B, Longaker MT. Deleterious effects of freezing on osteogenic differentiation of human adipose-derived stromal cells in vitro and in vivo.. Stem Cells Dev 20, 427–439.
- Schnabel LV, Pezzanite LM, Antczak DF, Felippe MJ, Fortier LA. Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro.. Stem Cell Res Ther 5, 13.
- Barberini DJ, Freitas NP, Magnoni MS, Maia L, Listoni AJ, Heckler MC, Sudano MJ, Golim MA, da Cruz Landim-Alvarenga F, Amorim RM. Equine mesenchymal stem cells from bone marrow, adipose tissue and umbilical cord: immunophenotypic characterization and differentiation potential.. Stem Cell Res Ther 5, 25.
- Mundy LN, Ishihara A, Wellman ML, Bertone AL. Evaluation of the ability of a gravitational filtration system to enhance recovery of equine bone marrow elements.. Am J Vet Res 76, 561–569.
- Burk J, Berner D, Brehm W, Hillmann A, Horstmeier C, Josten C, Paebst F, Rossi G, Schubert S, Ahrberg AB. Long-Term Cell Tracking Following Local Injection of Mesenchymal Stromal Cells in the Equine Model of Induced Tendon Disease.. Cell Transplant 25, 2199–2211.
- Sullivan C, Barry F, Ritter T, O’Flatharta C, Howard L, Shaw G, Anegon I, Murphy M. Allogeneic murine mesenchymal stem cells: migration to inflamed joints in vivo and amelioration of collagen induced arthritis when transduced to express CTLA4Ig.. Stem Cells Dev 22, 3203–3213.
- Park YB, Ha CW, Kim JA, Han WJ, Rhim JH, Lee HJ, Kim KJ, Park YG, Chung JY. Single-stage cell-based cartilage repair in a rabbit model: cell tracking and in vivo chondrogenesis of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel composite.. Osteoarthritis Cartilage 25, 570–580.
- Ikuta Y, Kamei N, Ishikawa M, Adachi N, Ochi M. In Vivo Kinetics of Mesenchymal Stem Cells Transplanted into the Knee Joint in a Rat Model Using a Novel Magnetic Method of Localization.. Clin Transl Sci 8, 467–474.
- Delling U, Brehm W, Metzger M, Ludewig E, Winter K, Julke H. In vivo tracking and fate of intra-articularly injected superparamagnetic iron oxide particle-labeled multipotent stromal cells in an ovine model of osteoarthritis.. Cell Transplant 24, 2379–2390.
- Li M, Luo X, Lv X, Liu V, Zhao G, Zhang X, Cao W, Wang R, Wang W. In vivo human adipose-derived mesenchymal stem cell tracking after intra-articular delivery in a rat osteoarthritis model.. Stem Cell Res Ther 7, 160.
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