Allogeneic vs. autologous intra‐articular mesenchymal stem cell injection within normal horses: Clinical and cytological comparisons suggest safety

Abstract

Summary Background Allogeneic bone marrow‐derived mesenchymal stem cells (BMDMSCs) could provide multiple advantages over autologous BMDMSCs, including creating an ‘off‐the‐shelf’ treatment together with the ability to control for donor variation. Objectives The objective of the study was to compare the clinical and synovial fluid response of the normal equine joint to autologous and pooled‐allogeneic BMDMSCs while controlling for individual variation and joint variations in response to intra‐articular injections. We hypothesised that, by controlling for individual animal and joint variation, we could identify differences between allogeneic vs. autologous BMDMSCs in noninflamed joints. Study design Randomised‐controlled experiment. Methods Bone marrow was harvested from eight horses. Autologous BMDMSCs were culture expanded, cryopreserved and thawed immediately prior to administration. For allogeneic BMDMSC treatments, four horses' BMDMSCs were culture expanded, pooled, cryopreserved and thawed immediately prior to use. Ten million (autologous or pooled‐allogeneic) BMDMSCs were administered into contralateral forelimb metacarpophalangeal joints so that every autologous and allogeneic injection could be compared within the same animal. Clinical parameters included subjective lameness, objective lameness (Lameness Locator™), response to flexion, joint circumference and joint effusion. Arthrocentesis was performed for assessment of the nucleated cell count, differential cell count, total protein, and synovial concentrations of prostaglandin E2 (PGE2) and c‐reactive protein (CRP). All parameters were measured at baseline, 6, 12, 24, 72, 168 and 336 h post‐injection. Results No difference was detected in any parameters between forelimb metacarpophalangeal joints administered autologous or pooled‐allogeneic BMDMSCs. Main limitations This study did not attempt to measure efficacy of BMDMSCs for musculoskeletal disease and should be followed by properly controlled efficacy trials. Conclusions The study did not identify any clinical or cytological differences in the normal joint response to allogeneic or autologous BMDMSCs. A larger study to prove equivalence is warranted as allogeneic BMDMSCs may be a feasible alternative to autologous BMDMSCs.

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

“…In fact, at a single time point (6 hours) post‐injection, an increase in subjective lameness was appreciated in both the AUTO‐ and ALLO‐treated groups compared to horses treated with rIL‐1β alone. Although not substantiated by objective lameness data, this result is consistent with previous studies of intra‐articular administration which found that BMDMSCs may result in an inflammatory effect . A single previous study in horses evaluated the use of umbilical‐derived MSCs in a lipopolysaccharide (LPS)‐induced inflammatory joint model.…”

“…Because of this, treatments directed against IL‐1β, such as IL‐1β receptor antagonist protein, have resulted in improved clinical outcomes and disease‐modifying effects . Although BMDMSCs have been increasingly used as an anti‐inflammatory joint therapy, intra‐articular administration has been found to result in an inflammatory response in normal joints . Furthermore, no studies have investigated the effect of BMDMSCs in an inflammatory model of disease.…”

Effects of Normal Synovial Fluid and Interferon Gamma on Chondrogenic Capability and Immunomodulatory Potential Respectively on Equine Mesenchymal Stem Cells

“…Furthermore, in order to improve the feasibility of using these in the clinic, we chose to evaluate MSCs derived from the same recipient donor (autologous) or another donor (allogeneic) [34]. Autologous MSCs have a less immunologic reaction; however, using these MSCs has proven to be costly and time-consuming in vitro [17]. While allogeneic MSCs have the advantage to offer an "offthe-shelf" therapy, their safety must be well established before clinical use.…”

“…Data also indicate that exposing MSCs to synovial fluid might alter their chondrogenesis phenotype and, as a result, the response of MSCs to synovial fluid is not consistent. In equines, autologous and allogeneic MSCs can be used for the treatment of musculoskeletal disorders [17], modifying inflammatory processes [18] and have demonstrated no adverse immunological reactions to intra-articular injection [19]. Therefore, the first aim of our study is designed to determine the survival rate and chondrogenic effects of autologous and allogenic synovial fluid on equine BMMSCs.…”

Exosome therapeutics for lung regenerative medicine

“…Although the immunogenicity, safety, and efficacy of exosomes from xenogeneic and allogenic sources have not been fully characterized, numerous preclinical studies have made such evaluations in cellular therapies. With studies showing disease improvement in both allogeneic and autologous treatments, it is promising that pre-clinical studies using exosomes from such cellular sources would better overcome regulatory hurdles when translated to a clinical setting [48,74,75]. Since some exosome studies have shown unaffected differentially expressed genes related to inflammation or toxicity, as well as no visual signs of toxicity after repeated administration, exosome therapies show promise [76,77].…”