Trends in Biotechnology
Volume 25, Issue 9, September 2007, Pages 409-416
Journal home page for Trends in Biotechnology

Review
Stem cells in veterinary medicine – attempts at regenerating equine tendon after injury

https://doi.org/10.1016/j.tibtech.2007.07.009Get rights and content

Stem cells have evoked considerable excitement in the animal-owning public because of the promise that stem cell technology could deliver tissue regeneration for injuries for which natural repair mechanisms do not deliver functional recovery and for which current therapeutic strategies have minimal effectiveness. This review focuses on the current use of stem cells within veterinary medicine, whose practitioners have used mesenchymal stem cells (MSCs), recovered from either bone marrow or adipose tissue, in clinical cases primarily to treat strain-induced tendon injury in the horse. The background on why this treatment has been advocated, the data supporting its use and the current encouraging outcome from clinical use in horses treated with bone-marrow-derived cells are presented together with the future challenges of stem-cell therapy for the veterinary community.

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.

References (75)

  • A.A. Worster

    Chondrocytic differentiation of mesenchymal stem cells sequentially exposed to transforming growth factor-beta1 in monolayer and insulin-like growth factor-I in a three-dimensional matrix

    J. Orthop. Res.

    (2001)
  • C. Shukunami

    Molecular cloning of tenomodulin, a novel chondromodulin-I related gene

    Biochem. Biophys. Res. Commun.

    (2001)
  • Y. Asou

    Coordinated expression of scleraxis and Sox9 genes during embryonic development of tendons and cartilage

    J. Orthop. Res.

    (2002)
  • D. Turhani

    Analysis of cell-seeded 3-dimensional bone constructs manufactured in vitro with hydroxyapatite granules obtained from red algae

    J. Oral Maxillofac. Surg.

    (2005)
  • K. Uematsu

    Cartilage regeneration using mesenchymal stem cells and a three-dimensional poly-lactic-glycolic acid (PLGA) scaffold

    Biomaterials

    (2005)
  • L. Qian et al.

    Improving the expansion and neuronal differentiation of mesenchymal stem cells through culture surface modification

    Biomaterials

    (2004)
  • A.E. Goodship

    The pathobiology and repair of tendon and ligament injury

    Vet. Clin. North Am. Equine Pract.

    (1994)
  • I.F. Williams

    Cell morphology and collagen types in equine tendon scar

    Res. Vet. Sci.

    (1980)
  • J.H. Wang

    Mechanobiology of tendon

    J. Biomech.

    (2006)
  • R.K.W. Smith et al.

    Tendon and ligament physiology

  • K.H. Kraus et al.

    Mesenchymal stem cells and bone regeneration

    Vet. Surg.

    (2006)
  • M.M. Wilke

    Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model

    J. Orthop. Res.

    (2007)
  • B.A. Dowling

    Superficial digital flexor tendonitis in the horse

    Equine Vet. J.

    (2000)
  • J. Huard

    Muscle-derived stem cells: potential for muscle regeneration

    Birth Defects Res. C Embryo Today

    (2003)
  • L. da Silva Meirelles

    Mesenchymal stem cells reside in virtually all post-natal organs and tissues

    J. Cell Sci.

    (2006)
  • A. Barbero

    Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes

    Arthritis Rheum.

    (2003)
  • B.L. Yen

    Isolation of multipotent cells from human term placenta

    Stem Cells

    (2005)
  • S. Strassburg

    Adult and late foetal equine tendon contain cell populations with weak progenitor properties in comparison to bone marrow derived mesenchymal stem cells

    Proceedings of the 52nd Orthopaedic Research Society

    (2006)
  • J. Park

    Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells

    J. Gene Med.

    (2006)
  • S.A. Goodman

    Tenocyte response to cyclical strain and transforming growth factor beta is dependent upon age and site of origin

    Biorheology

    (2004)
  • W. Liu

    Repair of tendon defect with dermal fibroblast engineered tendon in a porcine model

    Tissue Eng.

    (2006)
  • A.I. Caplan

    Mesenchymal stem cells and tissue repair

  • G. Ferrari

    Muscle regeneration by bone marrow-derived myogenic progenitors

    Science

    (1998)
  • R.G. Young

    Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair

    J. Orthop. Res.

    (1998)
  • H.A. Awad

    Autologous mesenchymal stem cell-mediated repair of tendon

    Tissue Eng.

    (1999)
  • A.K. Chong

    Bone marrow-derived mesenchymal stem cells influence early tendon-healing in a rabbit Achilles tendon model

    J. Bone Joint Surg. Am.

    (2007)
  • K.A. Hildebrand

    Response of donor and recipient cells after transplantation of cells to the ligament and tendon

    Microsc. Res. Tech.

    (2002)
  • Cited by (0)

    View full text