Trends in Biotechnology
ReviewStem cells in veterinary medicine – attempts at regenerating equine tendon after injury
Section snippets
Current diseases in veterinary medicine for which stem-cell technologies are being considered
Much of the interest in the veterinary field is centred on the use of stem cells for orthopaedic injury and, in terms of translational research for developing the technology for use in the clinic, the most advanced application has been in the horse. Stem cells have been used for studies of heart disease in dogs, although this has been mainly as a model for ischaemic heart disease in man [1]. Unlike humans, most other mammals, including dogs, do not suffer naturally occurring clinical ischaemic
Rationale behind the use of exogenous stem cells for treating over-strain injuries of the superficial digital flexor tendon
Tendon naturally heals (repairs) well, but the scar tissue formed in this repair is functionally deficient in comparison to normal tendon; this has important consequences for the animal in terms of reduced performance and a substantial risk of re-injury [5]. Because pain is not a feature of this condition in the horse, other than in the initial stages (see Box 2), treatments are aimed at restoring functionality. However, there is little evidence that any of the currently available treatments
What stem cell sources have been considered for use in horses?
Embryonic stem cells offer great potential because they are pluripotential, but they have the disadvantages of being allogenic (although with greater immunological tolerance) and being associated with a risk of teratoma formation; therefore, these cells are currently not used clinically, although recent work suggests future possibilities 29, 30, 31.
MSCs are found in the BM and in small amounts in other tissues, as well as in peripheral blood [32] and the umbilical cord 33, 34. Lee et al.[33]
Can stem cells make tendon? – in vitro evidence of tenogenesis
MSCs cultured in 2D and 3D matrices can be induced to synthesize matrices with some (but not all) of the characteristics of tendon ECM. We have found that equine MSCs can synthesize an abundant and remarkably well-structured matrix when cultured in vitro in a bioreactor within the coagulated supernatant of the BM (Figure 4). However, although several confident determinants of osteogenic, lipidogenic and chondrogenic differentiation are available, demonstration of tenogenic differentiation has
Can stem cells make tendon? – in vivo evidence
Tissue regeneration is thought to require four separate but synergistic elements. There must be a scaffold that will accommodate the cell source to provide protection and nutrition, an appropriate mix of anabolic factors to encourage ECM formation, an appropriate mechanical environment to provide organizational cues and a cell source. Both Cao et al.[54] and Juncosa-Melvin et al.[55] demonstrated that implanting autologous cells with a scaffold would bridge a tendon defect with better
Why the horse? – Disease features that lend themselves to cell therapy
The experimental assessment of tenogenesis by stem cells has utilized laceration injuries in laboratory animals, where maintaining the cells within the laceration site requires some sort of construct, which can also exert an influence, either positively or negatively. By contrast, equine digital-flexor-tendon strain injuries have a different aetiopathogenesis and provide many of the elements required for tendon-tissue engineering – the lesion manifests within the central core of the tissue and
Future challenges
Although it has not been possible to demonstrate that the implanted cells survive and synthesize a tendon-like matrix in horse tendon, studies in other species and for other tissues confirm that implanted cells do survive 25, 53, 62. Mechanical testing and biochemical and molecular analysis of the new tissue synthesized after treatment will help to determine whether the resulting tissue is of better ‘quality’ than untreated scar tissue. The use of these markers will enable better
Conclusions
Our clinical experience has, so far, been encouraging with this technology, although proof of efficacy, essential before full confidence in the technology can be achieved, is still lacking. Although cell-based therapies are likely to be another instrument for tackling orthopaedic disease in the future, it is also likely that we will need to be selective in choosing the right clinical cases. It is hoped that experience gained from treating clinical cases in horses will provide sufficient
Acknowledgements
The authors would like to acknowledge the sources of funding that have provided the basis for this work: The Horserace Betting Levy Board and the Pet Plan Charitable Trust. R.K.W.S. is a director of VetCell Bioscience Ltd.
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