Beneficial Effects of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Naturally Occurring Tendinopathy

Abstract

Tendon injuries are a common age-related degenerative condition where current treatment strategies fail to restore functionality and normal quality of life. This disease also occurs naturally in horses, with many similarities to human tendinopathy making it an ideal large animal model for human disease. Regenerative approaches are increasingly used to improve outcome involving mesenchymal stem cells (MSCs), supported by clinical data where injection of autologous bone marrow derived MSCs (BM-MSCs) suspended in marrow supernatant into injured tendons has halved the re-injury rate in racehorses. We hypothesized that stem cell therapy induces a matrix more closely resembling normal tendon than the fibrous scar tissue formed by natural repair. Twelve horses with career-ending naturally-occurring superficial digital flexor tendon injury were allocated randomly to treatment and control groups. 1X107 autologous BM-MSCs suspended in 2 ml of marrow supernatant were implanted into the damaged tendon of the treated group. The control group received the same volume of saline. Following a 6 month exercise programme horses were euthanized and tendons assessed for structural stiffness by non-destructive mechanical testing and for morphological and molecular composition.BM-MSC treated tendons exhibited statistically significant improvements in key parameters compared to saline-injected control tendons towards that of normal tendons and those in the contralateral limbs. Specifically, treated tendons had lower structural stiffness (p<0.05) although no significant difference in calculated modulus of elasticity, lower (improved) histological scoring of organisation (p<0.003) and crimp pattern (p<0.05), lower cellularity (p<0.007), DNA content (p<0.05), vascularity (p<0.03), water content (p<0.05), GAG content (p<0.05), and MMP-13 activity (p<0.02).Treatment with autologous MSCs in marrow supernatant therefore provides significant benefits compared to untreated tendon repair in enhancing normalisation of biomechanical, morphological, and compositional parameters. These data in natural disease, with no adverse findings, support the use of this treatment for human tendon injuries.

Comparative immunophenotyping of equine multipotent mesenchymal stromal cells: An approach toward a standardized definition

“…Using the horse as a model in clinical and experimental studies, promising results have been obtained with the therapeutical usage of MSCs for orthopedic disorders. In particular, MSC treatment of equine tendinopathy yielded lower re-injury rates (23)(24)(25)(26) and an improved tendon structure (27)(28)(29). Therefore, the therapeutic results achieved in equine athletes during the last decade could be valuable in human medicine as well.…”

Stem cell-based tissue engineering in veterinary orthopaedics

“…In histological sections of MSC-treated tendon lesions, compared to non-treated tendon lesions, increased tendon fiber densities, increased organization of the collagen fibers and a reduced vascularity could be found (Nixon et al 2008;Schnabel et al 2009;Smith et al 2009). However, statistically significant differences could neither be detected in DNA, proteoglycan, or total collagen content, nor in the expressions of type I collagen, type III collagen, or tissue remodeling enzymes such as matrix metalloproteinases (Nixon et al 2008;Schnabel et al 2009), suggesting that the beneficial effect of MSC is due to improvement of structural organization rather than of matrix composition.…”

Exposure of a tendon extracellular matrix to synovial fluid triggers endogenous and engrafted cell death: A mechanism for failed healing of intrathecal tendon injuries

“…Enhancing natural tendon repair using autologous bone marrow-derived MSCs is an attractive concept, which is supported by positive results in both clinical and experimental studies in the horse but to date these have been limited to extra-synovial tendon injuries [19,20]. Little is currently known about the effect of synovial fluid on implanted cells.…”