Pluripotent Stem Cells: The Future of Articular Cartilage Repair in Horses?

Scientific Literature Review:

Articular cartilage repair in horses and its new developments:
Pluripotent stem cells: the future of articular cartilage repair in the horse?

3rd year veterinary medicine student, Faculty of Veterinary Medicine,
University of Utrecht, Utrecht, The Netherlands.

Abstract
Articular cartilage is a unique connective tissue that is responsible for smoothly transferring variable loads between articulating bones. It is well known that cartilage has an extremely limited healing capacity thus once cartilage is injured it rarely heals properly. Consequently, cartilage injuries result in permanent loss of function, which can ultimately lead to euthanasia in athletic horses. The significant amount of horses and money lost as a consequence of these injuries is a strong motivation to find a treatment that will overcome the obstacles of cartilage healing. Unfortunately, current clinically used cartilage injury treatments have failed to provide functional hyaline-like repair tissue. It is for this reason that the interest in stem cells and their use medicinally has grown immensely over the years. The objective of stem cell-assisted regenerative therapy is to restore cartilage to its normal and completely functional state by harnessing the regenerative nature of stem cells to produce healthy functional chondrocytes and replace injured or defective tissues. Stem cells (embryonic-, adult- or induced) have shown great potential for healing cartilage injuries thus saving the horse racing industry a lot of capital and sparing the lives of many injured horses. In this article, current therapies for cartilage repair are reviewed and future prospects for the use of embryonic stem cells are identified.

Cartilage:
Cartilage is a strong yet flexible connective tissue capable of withstanding large amounts of force and mechanical stress (Desjardins and Hurtig 1990). These attributes are appropriate for articular cartilage

References: Bodo G, Hangody L, Modis L, Hurtig M. 2004. Autologous osteochondral grafting (mosaic arthroplasty) for treatment of subchondral cystic lesions in the equine stifle and fetlock joints. Vet Surg 33(6):588-96. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. 1994. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331(14):889-95. Carey BW, Markoulaki S, Hanna J, Saha K, Gao Q, Mitalipova M, Jaenisch R. 2009. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci U S A 106(1):157-62. Chu CR, Szczodry M, Bruno S. 2010. Animal models for cartilage regeneration and repair. Tissue Eng Part B Rev 16(1):105-15. Chung C and Burdick JA. 2008. Engineering cartilage tissue. Adv Drug Deliv Rev 60(2):243-62. Desjardins MR and Hurtig MB. 1990. Cartilage healing a review with emphasis on the equine model. Canadian Veterinary Journal 31(8):565-72. Fortier LA, Nixon AJ, Williams J, Cable CS. 1998. Isolation and chondrocytic differentiation of equine bone marrow-derived mesenchymal stem cells. Am J Vet Res 59(9):1182-7. Getgood A, Brooks R, Fortier L, Rushton N. 2009. Articular cartilage tissue engineering: Today 's research, tomorrow 's practice? J Bone Jt Surg Ser B 91(5):565-76. Hangody L, Vásárhelyi G, Hangody LR, Sükösd Z, Tibay G, Bartha L, Bodó G. 2008. Autologous osteochondral grafting-technique and long-term results. Injury 39(1 SUPPL.):32-9. Hegewald AA, Ringe J, Bartel J, Kruger I, Notter M, Barnewitz D, Kaps C, Sittinger M. 2004. Hyaluronic acid and autologous synovial fluid induce chondrogenic differentiation of equine mesenchymal stem cells: A preliminary study. Tissue Cell 36(6):431-8. Hoben GM, Willard VP, Athanasiou KA. 2009. Fibrochondrogenesis of hESCs: Growth factor combinations and cocultures. Stem Cells Dev 18(2):283-92. Hunziker EB. 2002. Articular cartilage repair: Basic science and clinical progress. A review of the current status and prospects. Osteoarthritis Cartilage 10(6):432-63. Kawaguchi J, Mee PJ, Smith AG. 2005. Osteogenic and chondrogenic differentiation of embryonic stem cells in response to specific growth factors. Bone 36(5):758-69. Kerker JT, Leo AJ, Sgaglione NA. 2008. Cartilage repair: Synthetics and scaffolds: Basic science, surgical techniques, and clinical outcomes. Sports Med Arthrosc 16(4):208-16. Kiskinis E and Eggan K. 2010. Progress toward the clinical application of patient-specific pluripotent stem cells. J Clin Invest 120(1):51-9. Koch TG, Berg LC, Betts DH. 2009. Current and future regenerative medicine - principles, concepts, and therapeutic use of stem cell therapy and tissue engineering in equine medicine. Canadian Veterinary Journal 50(2):155-65. Koch TG and Betts DH. 2007. Stem cell therapy for joint problems using the horse as a clinically relevant animal model. Expert Opin Biol Ther 7(11):1621-6. Koelling S and Miosge N. 2009. Stem cell therapy for cartilage regeneration in osteoarthritis. Expert Opin Biol Ther 9(11):1399-405. Kramer J, Schlenke P, Rohwedel J. 2007. Induction of ES cell-derived cartilage formation. Curr Protoc Cell Biol Chapter 23. Kramer J, Böhrnsen F, Schlenke P, Rohwedel J. 2006. Stem cell-derived chondrocytes for regenerative medicine. Transplant Proc 38(3):762-5. Kramer J, Klinger M, Kruse C, Faza M, Hargus G, Rohwedel J. 2005. Ultrastructural analysis of mouse embryonic stem cell-derived chondrocytes. Anat Embryol (Berl) 210(3):175-85. Lee KBL, Hui JHP, Im CS, Ardany L, Eng HL. 2007. Injectable mesenchymal stem cell therapy for large cartilage defects - A porcine model. Stem Cells 25(11):2964-71. Nakayama N, Duryea D, Manoukian R, Chow G, Han C-E. 2003. Microscopic cartilage formation with embryonic stem-cell-derived mesodermal progenitor cells. J Cell Sci 116(10):2015-28. Paris DB and Stout TA. 2010. Equine embryos and embryonic stem cells: Defining reliable markers of pluripotency. Theriogenology . Riggs CM. 2006. Osteochondral injury and joint disease in the athletic horse. Equine Veterinary Education 18(2):100-12. Saito S, Ugai H, Sawai K, Yamamoto Y, Minamihashi A, Kurosaka K, Kobayashi Y, Murata T, Obata Y, Yokoyama K. 2002. Isolation of embryonic stem-like cells from equine blastocysts and their differentiation in vitro. FEBS Lett 531(3):389-96. Stewart AA, Byron CR, Pondenis H, Stewart MC. 2007. Effect of fibroblast growth factor-2 on equine mesenchymal stem cell monolayer expansion and chondrogenesis. Am J Vet Res 68(9):941-5. Taylor SE, Smith RK, Clegg PD. 2007. Mesenchymal stem cell therapy in equine musculoskeletal disease: Scientific fact or clinical fiction? Equine Vet J 39(2):172-80. Tecirlioglu RT and Trounson AO. 2007. Embryonic stem cells in companion animals (horses, dogs and cats): Present status and future prospects. Reprod Fertil Dev 19(6):740-7. Wilke MM, Nydam DV, Nixon AJ. 2007. Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model. J Orthop Res 25(7):913-25. Williams RB, Harkins LS, Hammond CJ, Wood JL. 2001. Racehorse injuries, clinical problems and fatalities recorded on british racecourses from flat racing and national hunt racing during 1996, 1997 and 1998. Equine Vet J 33(5):478-86. Wilsher S, Allen WR, Wood JL. 2006. Factors associated with failure of thoroughbred horses to train and race. Equine Vet J 38(2):113-8. Worster AA, Nixon AJ, Brower-Toland BD, Williams J. 2000. Effect of transforming growth factor β1 on chondrogenic differentiation of cultured equine mesenchymal stem cells. Am J Vet Res 61(9):1003-10. Xie F, Zhang W, Chen F, Zhou G, Cui L, Liu W, Cao Y. 2008. Chondrogenic differentiation of mouse embryonic stem cells promoted by mature chondrocytes. Sci China Ser C Life Sci 51(9):774-8. Zhu X-, Pan X-, Wang W, Chen Q, Pang R-, Cai X-, Hoffman AR, Hu J-. 2010. Transient in vitro epigenetic reprogramming of skin fibroblasts into multipotent cells. Biomaterials 31(10):2779-87.