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Challenges of stem cell therapies in companion animal practice

  • Kang, Min-Hee (Department of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University) ;
  • Park, Hee-Myung (Department of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University)
  • Received : 2018.09.21
  • Accepted : 2020.03.17
  • Published : 2020.05.31

Abstract

Regenerative medicine using stem cells from various sources are emerging treatment modality in several refractory diseases in veterinary medicine. It is well-known that stem cells can differentiate into specific cell types, self-renew, and regenerate. In addition, the unique immunomodulatory effects of stem cells have made stem cell transplantation a promising option for treating a wide range of disease and injuries. Recently, the medical demands for companion animals have been rapidly increasing, and certain disease conditions require alternative treatment options. In this review, we focused on stem cell application research in companion animals including experimental models, case reports and clinical trials in dogs and cats. The clinical studies and therapeutic protocols were categorized, evaluated and summarized according to the organ systems involved. The results indicate that evidence for the effectiveness of cell-based treatment in specific diseases or organ systems is not yet conclusive. Nonetheless, stem cell therapy may be a realistic treatment option in the near future, therefore, considerable efforts are needed to find optimized cell sources, cell numbers and delivery methods in order to standardize treatment methods and evaluation processes.

Keywords

Acknowledgement

The authors thanks to the members of our internal medicine laboratory for their support during drafting of this manuscript.

References

  1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143-147. https://doi.org/10.1126/science.284.5411.143
  2. Gotherstrom C. Immunomodulation by multipotent mesenchymal stromal cells. Transplantation. 2007;84(1 Suppl):S35-S37. https://doi.org/10.1097/01.tp.0000269200.67707.c8
  3. Mizuno H. Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med Sch. 2009;76(2):56-66. https://doi.org/10.1272/jnms.76.56
  4. Ozawa K, Sato K, Oh I, Ozaki K, Uchibori R, Obara Y, Kikuchi Y, Ito T, Okada T, Urabe M, Mizukami H, Kume A. Cell and gene therapy using mesenchymal stem cells (MSCs). J Autoimmun. 2008;30(3):121-127. https://doi.org/10.1016/j.jaut.2007.12.008
  5. Barker RA. Developing stem cell therapies for Parkinson's disease: waiting until the time is right. Cell Stem Cell. 2014;15(5):539-542. https://doi.org/10.1016/j.stem.2014.09.016
  6. Li C, Dong N, Wu H, Dong F, Xu Y, Du H, He H, Liu Z, Li W. A novel method for preservation of human corneal limbal tissue. Invest Ophthalmol Vis Sci. 2013;54(6):4041-4047. https://doi.org/10.1167/iovs.13-11648
  7. Mitchell A, Fujisawa T, Newby D, Mills N, Cruden NL. Vascular injury and repair: a potential target for cell therapies. Future Cardiol. 2015;11(1):45-60. https://doi.org/10.2217/fca.14.77
  8. Murphy SV, Kidyoor A, Reid T, Atala A, Wallace EM, Lim R. Isolation, cryopreservation and culture of human amnion epithelial cells for clinical applications. J Vis Exp. 2014;94(94):52085.
  9. Schwartz SD, Hubschman JP, Heilwell G, Franco-Cardenas V, Pan CK, Ostrick RM, Mickunas E, Gay R, Klimanskaya I, Lanza R. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379(9817):713-720. https://doi.org/10.1016/S0140-6736(12)60028-2
  10. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21(14):2724-2752. https://doi.org/10.1089/scd.2011.0722
  11. Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874-882. https://doi.org/10.1002/ana.20501
  12. Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke. 2001;32(4):1005-1011. https://doi.org/10.1161/01.STR.32.4.1005
  13. Furlani D, Ugurlucan M, Ong L, Bieback K, Pittermann E, Westien I, Wang W, Yerebakan C, Li W, Gaebel R, Li RK, Vollmar B, Steinhoff G, Ma N. Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy. Microvasc Res. 2009;77(3):370-376. https://doi.org/10.1016/j.mvr.2009.02.001
  14. Kang WJ, Kang HJ, Kim HS, Chung JK, Lee MC, Lee DS. Tissue distribution of 18F-FDG-labeled peripheral hematopoietic stem cells after intracoronary administration in patients with myocardial infarction. J Nucl Med. 2006;47(8):1295-1301.
  15. Kursova LV, Konoplyannikov AG, Pasov VV, Ivanova IN, Poluektova MV, Konoplyannikova OA. Possibilities for the use of autologous mesenchymal stem cells in the therapy of radiation-induced lung injuries. Bull Exp Biol Med. 2009;147(4):542-546. https://doi.org/10.1007/s10517-009-0538-7
  16. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24(5):1294-1301. https://doi.org/10.1634/stemcells.2005-0342
  17. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317. https://doi.org/10.1080/14653240600855905
  18. Alves EG, Serakides R, Boeloni JN, Rosado IR, Ocarino NM, Oliveira HP, Goes AM, Rezende CM. Comparison of the osteogenic potential of mesenchymal stem cells from the bone marrow and adipose tissue of young dogs. BMC Vet Res. 2014;10(1):190. https://doi.org/10.1186/s12917-014-0190-y
  19. Marx C, Silveira MD, Beyer Nardi N. Adipose-derived stem cells in veterinary medicine: characterization and therapeutic applications. Stem Cells Dev. 2015;24(7):803-813. https://doi.org/10.1089/scd.2014.0407
  20. Vulliet PR, Greeley M, Halloran SM, MacDonald KA, Kittleson MD. Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet. 2004;363(9411):783-784. https://doi.org/10.1016/S0140-6736(04)15695-X
  21. Kang MH, Park HM. Evaluation of adverse reactions in dogs following intravenous mesenchymal stem cell transplantation. Acta Vet Scand. 2014;56(1):16. https://doi.org/10.1186/1751-0147-56-16
  22. Black LL, Gaynor J, Gahring D, Adams C, Aron D, Harman S, Gingerich DA, Harman R. Effect of adiposederived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized, double-blinded, multicenter, controlled trial. Vet Ther. 2007;8(4):272-284.
  23. Hall MN, Rosenkrantz WS, Hong JH, Griffin CE, Mendelsohn CM. Evaluation of the potential use of adipose-derived mesenchymal stromal cells in the treatment of canine atopic dermatitis: a pilot study. Vet Ther. 2010;11(2):E1-E14.
  24. Marx C, Silveira MD, Selbach I, da Silva AS, Braga LM, Camassola M, Nardi NB. Acupoint injection of autologous stromal vascular fraction and allogeneic adipose-derived stem cells to treat hip dysplasia in dogs. Stem Cells Int. 2014;2014:391274.
  25. Vilar JM, Batista M, Morales M, Santana A, Cuervo B, Rubio M, Cugat R, Sopena J, Carrillo JM. Assessment of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells in osteoarthritic dogs using a double blinded force platform analysis. BMC Vet Res. 2014;10(1):143. https://doi.org/10.1186/1746-6148-10-143
  26. Vilar JM, Morales M, Santana A, Spinella G, Rubio M, Cuervo B, Cugat R, Carrillo JM. Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs. BMC Vet Res. 2013;9(1):131. https://doi.org/10.1186/1746-6148-9-131
  27. Gabel BC, Curtis EI, Marsala M, Ciacci JD. A review of stem cell therapy for spinal cord injury: large animal models and the frontier in humans. World Neurosurg. 2017;98:438-443. https://doi.org/10.1016/j.wneu.2016.11.053
  28. Fortier LA, Travis AJ. Stem cells in veterinary medicine. Stem Cell Res Ther. 2011;2(1):9. https://doi.org/10.1186/scrt50
  29. Markoski MM. Advances in the use of stem cells in veterinary medicine: from basic research to clinical practice. Scientifica (Cairo). 2016;2016:4516920.
  30. Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med. 1957;257(11):491-496. https://doi.org/10.1056/NEJM195709122571102
  31. Behfar A, Crespo-Diaz R, Terzic A, Gersh BJ. Cell therapy for cardiac repair--lessons from clinical trials. Nat Rev Cardiol. 2014;11(4):232-246. https://doi.org/10.1038/nrcardio.2014.9
  32. McMahill BG, Borjesson DL, Sieber-Blum M, Nolta JA, Sturges BK. Stem cells in canine spinal cord injury--promise for regenerative therapy in a large animal model of human disease. Stem Cell Rev Rep. 2015;11(1):180-193. https://doi.org/10.1007/s12015-014-9553-9
  33. Welt FG, Gallegos R, Connell J, Kajstura J, D'Amario D, Kwong RY, Coelho-Filho O, Shah R, Mitchell R, Leri A, Foley L, Anversa P, Pfeffer MA. Effect of cardiac stem cells on left-ventricular remodeling in a canine model of chronic myocardial infarction. Circ Heart Fail. 2013;6(1):99-106. https://doi.org/10.1161/CIRCHEARTFAILURE.112.972273
  34. Mahla RS. Stem cells applications in regenerative medicine and disease therapeutics. Int J Cell Biol. 2016;2016:6940283. https://doi.org/10.1155/2016/6940283
  35. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145-1147. https://doi.org/10.1126/science.282.5391.1145
  36. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-676. https://doi.org/10.1016/j.cell.2006.07.024
  37. Chauveau S, Anyukhovsky EP, Ben-Ari M, Naor S, Jiang YP, Danilo P Jr, Rahim T, Burke S, Qiu X, Potapova IA, Doronin SV, Brink PR, Binah O, Cohen IS, Rosen MR. Induced pluripotent stem cell-derived cardiomyocytes provide in vivo biological pacemaker function. Circ Arrhythm Electrophysiol. 2017;10(5):e004508. https://doi.org/10.1161/circep.116.004508
  38. Novak A, Shtrichman R, Germanguz I, Segev H, Zeevi-Levin N, Fishman B, Mandel YE, Barad L, Domev H, Kotton D, Mostoslavsky G, Binah O, Itskovitz-Eldor J. Enhanced reprogramming and cardiac differentiation of human keratinocytes derived from plucked hair follicles, using a single excisable lentivirus. Cell Reprogram. 2010;12(6):665-678. https://doi.org/10.1089/cell.2010.0027
  39. Segers VF, Lee RT. Stem-cell therapy for cardiac disease. Nature. 2008;451(7181):937-942. https://doi.org/10.1038/nature06800
  40. Perin EC, Silva GV, Assad JA, Vela D, Buja LM, Sousa AL, Litovsky S, Lin J, Vaughn WK, Coulter S, Fernandes MR, Willerson JT. Comparison of intracoronary and transendocardial delivery of allogeneic mesenchymal cells in a canine model of acute myocardial infarction. J Mol Cell Cardiol. 2008;44(3):486-495. https://doi.org/10.1016/j.yjmcc.2007.09.012
  41. Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D, Coulter SC, Lin J, Ober J, Vaughn WK, Branco RV, Oliveira EM, He R, Geng YJ, Willerson JT, Perin EC. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation. 2005;111(2):150-156. https://doi.org/10.1161/01.CIR.0000151812.86142.45
  42. Mitchell AJ, Sabondjian E, Sykes J, Deans L, Zhu W, Lu X, Feng Q, Prato FS, Wisenberg G. Comparison of initial cell retention and clearance kinetics after subendocardial or subepicardial injections of endothelial progenitor cells in a canine myocardial infarction model. J Nucl Med. 2010;51(3):413-417. https://doi.org/10.2967/jnumed.109.069732
  43. Wang X, Zhen L, Miao H, Sun Q, Yang Y, Que B, Lopes Lao EP, Wu X, Ren H, Shi S, Lau WB, Ma X, Ma C, Nie S. Concomitant retrograde coronary venous infusion of basic fibroblast growth factor enhances engraftment and differentiation of bone marrow mesenchymal stem cells for cardiac repair after myocardial infarction. Theranostics. 2015;5(9):995-1006. https://doi.org/10.7150/thno.11607
  44. Chang X, Liu J, Liao X, Liu G. Ultrasound-mediated microbubble destruction enhances the therapeutic effect of intracoronary transplantation of bone marrow stem cells on myocardial infarction. Int J Clin Exp Pathol. 2015;8(2):2221-2234.
  45. Hensley MT, Tang J, Woodruff K, Defrancesco T, Tou S, Williams CM, Breen M, Meurs K, Keene B, Cheng K. Intracoronary allogeneic cardiosphere-derived stem cells are safe for use in dogs with dilated cardiomyopathy. J Cell Mol Med. 2017;21(8):1503-1512. https://doi.org/10.1111/jcmm.13077
  46. Petchdee S, Sompeewong S. Intravenous administration of puppy deciduous teeth stem cells in degenerative valve disease. Vet World. 2016;9(12):1429-1434. https://doi.org/10.14202/vetworld.2016.1429-1434
  47. Driehuys S, Van Winkle TJ, Sammarco CD, Drobatz KJ. Myocardial infarction in dogs and cats: 37 cases (1985-1994). J Am Vet Med Assoc. 1998;213(10):1444-1448.
  48. Jung DI, Ha J, Kang BT, Kim JW, Quan FS, Lee JH, Woo EJ, Park HM. A comparison of autologous and allogenic bone marrow-derived mesenchymal stem cell transplantation in canine spinal cord injury. J Neurol Sci. 2009;285(1-2):67-77. https://doi.org/10.1016/j.jns.2009.05.027
  49. Lee JH, Chang HS, Kang EH, Chung DJ, Choi CB, Lee JH, Hwang SH, Han H, Kim HY. Percutaneous transplantation of human umbilical cord blood-derived multipotent stem cells in a canine model of spinal cord injury. J Neurosurg Spine. 2009;11(6):749-757. https://doi.org/10.3171/2009.6.SPINE08710
  50. Lee JH, Chung WH, Kang EH, Chung DJ, Choi CB, Chang HS, Lee JH, Hwang SH, Han H, Choe BY, Kim HY. Schwann cell-like remyelination following transplantation of human umbilical cord blood (hUCB)-derived mesenchymal stem cells in dogs with acute spinal cord injury. J Neurol Sci. 2011;300(1-2):86-96. https://doi.org/10.1016/j.jns.2010.09.025
  51. Lim JH, Byeon YE, Ryu HH, Jeong YH, Lee YW, Kim WH, Kang KS, Kweon OK. Transplantation of canine umbilical cord blood-derived mesenchymal stem cells in experimentally induced spinal cord injured dogs. J Vet Sci. 2007;8(3):275-282. https://doi.org/10.4142/jvs.2007.8.3.275
  52. Park SS, Byeon YE, Ryu HH, Kang BJ, Kim Y, Kim WH, Kang KS, Han HJ, Kweon OK. Comparison of canine umbilical cord blood-derived mesenchymal stem cell transplantation times: involvement of astrogliosis, inflammation, intracellular actin cytoskeleton pathways, and neurotrophin-3. Cell Transplant. 2011;20(11-12):1867-1880. https://doi.org/10.3727/096368911X566163
  53. Park SS, Lee YJ, Lee SH, Lee D, Choi K, Kim WH, Kweon OK, Han HJ. Functional recovery after spinal cord injury in dogs treated with a combination of matrigel and neural-induced adipose-derived mesenchymal stem cells. Cytotherapy. 2012;14(5):584-597. https://doi.org/10.3109/14653249.2012.658913
  54. Ryu HH, Kang BJ, Park SS, Kim Y, Sung GJ, Woo HM, Kim WH, Kweon OK. Comparison of mesenchymal stem cells derived from fat, bone marrow, Wharton's jelly, and umbilical cord blood for treating spinal cord injuries in dogs. J Vet Med Sci. 2012;74(12):1617-1630. https://doi.org/10.1292/jvms.12-0065
  55. Ryu HH, Lim JH, Byeon YE, Park JR, Seo MS, Lee YW, Kim WH, Kang KS, Kweon OK. Functional recovery and neural differentiation after transplantation of allogenic adipose-derived stem cells in a canine model of acute spinal cord injury. J Vet Sci. 2009;10(4):273-284. https://doi.org/10.4142/jvs.2009.10.4.273
  56. Kim BG, Kang YM, Phi JH, Kim YH, Hwang DH, Choi JY, Ryu S, Elastal AE, Paek SH, Wang KC, Lee SH, Kim SU, Yoon BW. Implantation of polymer scaffolds seeded with neural stem cells in a canine spinal cord injury model. Cytotherapy. 2010;12(6):841-845. https://doi.org/10.3109/14653249.2010.501784
  57. Lee SH, Chung YN, Kim YH, Kim YJ, Park JP, Kwon DK, Kwon OS, Heo JH, Kim YH, Ryu S, Kang HJ, Paek SH, Wang KC, Kim SU, Yoon BW. Effects of human neural stem cell transplantation in canine spinal cord hemisection. Neurol Res. 2009;31(9):996-1002. https://doi.org/10.1179/174313209X385626
  58. Besalti O, Aktas Z, Can P, Akpinar E, Elcin AE, Elcin YM. The use of autologous neurogenically-induced bone marrow-derived mesenchymal stem cells for the treatment of paraplegic dogs without nociception due to spinal trauma. J Vet Med Sci. 2016;78(9):1465-1473. https://doi.org/10.1292/jvms.15-0571
  59. Besalti O, Can P, Akpinar E, Aktas Z, Elcin AE, Elcin YM. Intraspinal transplantation of autologous neurogenically-induced bone marrow-derived mesenchymal stem cells in the treatment of paraplegic dogs without deep pain perception secondary to intervertebral disk disease. Turk Neurosurg. 2015;25(4):625-632.
  60. Granger N, Blamires H, Franklin RJ, Jeffery ND. Autologous olfactory mucosal cell transplants in clinical spinal cord injury: a randomized double-blinded trial in a canine translational model. Brain. 2012;135(Pt 11):3227-3237. https://doi.org/10.1093/brain/aws268
  61. Jeffery ND, Lakatos A, Franklin RJ. Autologous olfactory glial cell transplantation is reliable and safe in naturally occurring canine spinal cord injury. J Neurotrauma. 2005;22(11):1282-1293. https://doi.org/10.1089/neu.2005.22.1282
  62. Kim Y, Lee SH, Kim WH, Kweon OK. Transplantation of adipose derived mesenchymal stem cells for acute thoracolumbar disc disease with no deep pain perception in dogs. J Vet Sci. 2016;17(1):123-126. https://doi.org/10.4142/jvs.2016.17.1.123
  63. Nishida H, Nakayama M, Tanaka H, Kitamura M, Hatoya S, Sugiura K, Suzuki Y, Ide C, Inaba T. Evaluation of transplantation of autologous bone marrow stromal cells into the cerebrospinal fluid for treatment of chronic spinal cord injury in dogs. Am J Vet Res. 2011;72(8):1118-1123. https://doi.org/10.2460/ajvr.72.8.1118
  64. Nishida H, Nakayama M, Tanaka H, Kitamura M, Hatoya S, Sugiura K, Harada Y, Suzuki Y, Ide C, Inaba T. Safety of autologous bone marrow stromal cell transplantation in dogs with acute spinal cord injury. Vet Surg. 2012;41(4):437-442. https://doi.org/10.1111/j.1532-950X.2011.00959.x
  65. Penha EM, Meira CS, Guimaraes ET, Mendonca MV, Gravely FA, Pinheiro CM, Pinheiro TM, Barrouin-Melo SM, Ribeiro-Dos-Santos R, Soares MB. Use of autologous mesenchymal stem cells derived from bone marrow for the treatment of naturally injured spinal cord in dogs. Stem Cells Int. 2014;2014:437521. https://doi.org/10.1155/2014/437521
  66. Tamura K, Harada Y, Nagashima N, Itoi T, Ishino H, Yogo T, Nezu Y, Hara Y, Suzuki Y, Ide C, Tagawa M. Autotransplanting of bone marrow-derived mononuclear cells for complete cases of canine paraplegia and loss of pain perception, secondary to intervertebral disc herniation. Exp Clin Transplant. 2012;10(3):263-272. https://doi.org/10.6002/ect.2011.0151
  67. Cauzinille L, Kornegay JN. Fibrocartilaginous embolism of the spinal cord in dogs: review of 36 histologically confirmed cases and retrospective study of 26 suspected cases. J Vet Intern Med. 1996;10(4):241-245. https://doi.org/10.1111/j.1939-1676.1996.tb02056.x
  68. Chung WH, Park SA, Lee JH, Chung DJ, Yang WJ, Kang EH, Choi CB, Chang HS, Kim DH, Hwang SH, Han H, Kim HY. Percutaneous transplantation of human umbilical cord-derived mesenchymal stem cells in a dog suspected to have fibrocartilaginous embolic myelopathy. J Vet Sci. 2013;14(4):495-497. https://doi.org/10.4142/jvs.2013.14.4.495
  69. Chao YX, He BP, Tay SS. Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease. J Neuroimmunol. 2009;216(1-2):39-50. https://doi.org/10.1016/j.jneuroim.2009.09.003
  70. Parr AM, Tator CH, Keating A. Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant. 2007;40(7):609-619. https://doi.org/10.1038/sj.bmt.1705757
  71. Siniscalco D, Giordano C, Galderisi U, Luongo L, Alessio N, Di Bernardo G, de Novellis V, Rossi F, Maione S. Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice. Cell Mol Life Sci. 2010;67(4):655-669. https://doi.org/10.1007/s00018-009-0202-4
  72. Talarico LR, Schatzberg SJ. Idiopathic granulomatous and necrotising inflammatory disorders of the canine central nervous system: a review and future perspectives. J Small Anim Pract. 2010;51(3):138-149. https://doi.org/10.1111/j.1748-5827.2009.00823.x
  73. Uchida K, Park E, Tsuboi M, Chambers JK, Nakayama H. Pathological and immunological features of canine necrotising meningoencephalitis and granulomatous meningoencephalitis. Vet J. 2016;213:72-77. https://doi.org/10.1016/j.tvjl.2016.05.002
  74. Coates JR, Jeffery ND. Perspectives on meningoencephalomyelitis of unknown origin. Vet Clin North Am Small Anim Pract. 2014;44(6):1157-1185. https://doi.org/10.1016/j.cvsm.2014.07.009
  75. Genc B, Bozan HR, Genc S, Genc K. Stem cell therapy for multiple sclerosis. Adv Exp Med Biol. 2019;1084:145-174.
  76. Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol. 2007;61(3):219-227. https://doi.org/10.1002/ana.21076
  77. Nasri F, Mohtasebi MS, Hashemi E, Zarrabi M, Gholijani N, Sarvestani EK. Therapeutic efficacy of mesenchymal stem cells and mesenchymal stem cells-derived neural progenitors in experimental autoimmune encephalomyelitis. Int J Stem Cells. 2018;11(1):68-77. https://doi.org/10.15283/ijsc17052
  78. Zeira O, Asiag N, Aralla M, Ghezzi E, Pettinari L, Martinelli L, Zahirpour D, Dumas MP, Lupi D, Scaccia S, Konar M, Cantile C. Adult autologous mesenchymal stem cells for the treatment of suspected non-infectious inflammatory diseases of the canine central nervous system: safety, feasibility and preliminary clinical findings. J Neuroinflammation. 2015;12(1):181. https://doi.org/10.1186/s12974-015-0402-9
  79. Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol. 2009;10(3):207-217. https://doi.org/10.1038/nrm2636
  80. Branski LK, Gauglitz GG, Herndon DN, Jeschke MG. A review of gene and stem cell therapy in cutaneous wound healing. Burns. 2009;35(2):171-180. https://doi.org/10.1016/j.burns.2008.03.009
  81. Fathke C, Wilson L, Hutter J, Kapoor V, Smith A, Hocking A, Isik F. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells. 2004;22(5):812-822. https://doi.org/10.1634/stemcells.22-5-812
  82. Herdrich BJ, Lind RC, Liechty KW. Multipotent adult progenitor cells: their role in wound healing and the treatment of dermal wounds. Cytotherapy. 2008;10(6):543-550. https://doi.org/10.1080/14653240802345820
  83. Kim JW, Lee JH, Lyoo YS, Jung DI, Park HM. The effects of topical mesenchymal stem cell transplantation in canine experimental cutaneous wounds. Vet Dermatol. 2013;24(2):242-e53. https://doi.org/10.1111/vde.12011
  84. Zubin E, Conti V, Leonardi F, Zanichelli S, Ramoni R, Grolli S. Regenerative therapy for the management of a large skin wound in a dog. Clin Case Rep. 2015;3(7):598-603. https://doi.org/10.1002/ccr3.253
  85. Ribeiro J, Pereira T, Amorim I, Caseiro AR, Lopes MA, Lima J, Gartner A, Santos JD, Bartolo PJ, Rodrigues JM, Mauricio AC, Luis AL. Cell therapy with human MSCs isolated from the umbilical cord Wharton jelly associated to a PVA membrane in the treatment of chronic skin wounds. Int J Med Sci. 2014;11(10):979-987. https://doi.org/10.7150/ijms.9139
  86. Nam A, Han SM, Go DM, Kim DY, Seo KW, Youn HY. Long-term management with adipose tissue-derived mesenchymal stem cells and conventional treatment in a dog with hepatocutaneous syndrome. J Vet Intern Med. 2017;31(5):1514-1519. https://doi.org/10.1111/jvim.14798
  87. Hill PB, Auxilia ST, Munro E, Genovese L, Silkstone MA, Kirby B. Resolution of skin lesions and long-term survival in a dog with superficial necrolytic dermatitis and liver cirrhosis. J Small Anim Pract. 2000;41(11):519-523. https://doi.org/10.1111/j.1748-5827.2000.tb03976.x
  88. Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Quinn G, Okochi H, Ochiya T. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007;46(1):219-228. https://doi.org/10.1002/hep.21704
  89. Trebol Lopez J, Georgiev Hristov T, Garcia-Arranz M, Garcia-Olmo D. Stem cell therapy for digestive tract diseases: current state and future perspectives. Stem Cells Dev. 2011;20(7):1113-1129. https://doi.org/10.1089/scd.2010.0277
  90. Ibraheim H, Giacomini C, Kassam Z, Dazzi F, Powell N. Advances in mesenchymal stromal cell therapy in the management of Crohn's disease. Expert Rev Gastroenterol Hepatol. 2018;12(2):141-153. https://doi.org/10.1080/17474124.2018.1393332
  91. Schneider G, Saur D. Mesenchymal stem cells: therapeutic potential for acute pancreatitis. Gastroenterology. 2011;140(3):779-782. https://doi.org/10.1053/j.gastro.2011.01.026
  92. Alamoudi NM, El Ashiry EA, Farsi NM, El Derwi DA, Atta HM. Treatment of oral ulcers in dogs using adipose tissue-derived mesenchymal stem cells. J Clin Pediatr Dent. 2014;38(3):215-222. https://doi.org/10.17796/jcpd.38.3.193115427jg6vl60
  93. El-Menoufy H, Aly LA, Aziz MT, Atta HM, Roshdy NK, Rashed LA, Sabry D. The role of bone marrow-derived mesenchymal stem cells in treating formocresol induced oral ulcers in dogs. J Oral Pathol Med. 2010;39(4):281-289. https://doi.org/10.1111/j.1600-0714.2009.00819.x
  94. Jergens AE, Simpson KW. Inflammatory bowel disease in veterinary medicine. Front Biosci (Elite Ed). 2012;4(4):1404-1419. https://doi.org/10.2741/e470
  95. Perez-Merino EM, Uson-Casaus JM, Duque-Carrasco J, Zaragoza-Bayle C, Marinas-Pardo L, Hermida-Prieto M, Vilafranca-Compte M, Barrera-Chacon R, Gualtieri M. Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: endoscopic and histological outcomes. Vet J. 2015;206(3):391-397. https://doi.org/10.1016/j.tvjl.2015.07.023
  96. Perez-Merino EM, Uson-Casaus JM, Zaragoza-Bayle C, Duque-Carrasco J, Marinas-Pardo L, Hermida-Prieto M, Barrera-Chacon R, Gualtieri M. Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: clinical and laboratory outcomes. Vet J. 2015;206(3):385-390. https://doi.org/10.1016/j.tvjl.2015.08.003
  97. Hardie RJ, Gregory SP, Tomlin J, Sturgeon C, Lipscomb V, Ladlow J. Cyclosporine treatment of anal furunculosis in 26 dogs. J Small Anim Pract. 2005;46(1):3-9. https://doi.org/10.1111/j.1748-5827.2005.tb00267.x
  98. Day MJ, Weaver BM. Pathology of surgically resected tissue from 305 cases of anal furunculosis in the dog. J Small Anim Pract. 1992;33(12):583-589. https://doi.org/10.1111/j.1748-5827.1992.tb01062.x
  99. Massey J, Short AD, Catchpole B, House A, Day MJ, Lohi H, Ollier WE, Kennedy LJ. Genetics of canine anal furunculosis in the German shepherd dog. Immunogenetics. 2014;66(5):311-324. https://doi.org/10.1007/s00251-014-0766-5
  100. Ferrer L, Kimbrel EA, Lam A, Falk EB, Zewe C, Juopperi T, Lanza R, Hoffman A. Treatment of perianal fistulas with human embryonic stem cell-derived mesenchymal stem cells: a canine model of human fistulizing Crohn's disease. Regen Med. 2016;11(1):33-43. https://doi.org/10.2217/rme.15.69
  101. Webb TL, Webb CB. Stem cell therapy in cats with chronic enteropathy: a proof-of-concept study. J Feline Med Surg. 2015;17(10):901-908. https://doi.org/10.1177/1098612X14561105
  102. Arzi B, Clark KC, Sundaram A, Spriet M, Verstraete FJ, Walker NJ, Loscar MR, Fazel N, Murphy WJ, Vapniarsky N, Borjesson DL. Therapeutic efficacy of fresh, allogeneic mesenchymal stem cells for severe refractory feline chronic gingivostomatitis. Stem Cells Transl Med. 2017;6(8):1710-1722. https://doi.org/10.1002/sctm.17-0035
  103. Arzi B, Mills-Ko E, Verstraete FJ, Kol A, Walker NJ, Badgley MR, Fazel N, Murphy WJ, Vapniarsky N, Borjesson DL. Therapeutic efficacy of fresh, autologous mesenchymal stem cells for severe refractory gingivostomatitis in cats. Stem Cells Transl Med. 2016;5(1):75-86. https://doi.org/10.5966/sctm.2015-0127
  104. Lyon KF. Gingivostomatitis. Vet Clin North Am Small Anim Pract. 2005;35(4):891-911. https://doi.org/10.1016/j.cvsm.2005.02.001
  105. Liu C, Tan X, Luo J, Liu H, Hu M, Yue W. Reconstruction of beagle hemi-mandibular defects with allogenic mandibular scaffolds and autologous mesenchymal stem cells. PLoS One. 2014;9(8):e105733. https://doi.org/10.1371/journal.pone.0105733
  106. Wang Y, Bi X, Zhou H, Deng Y, Sun J, Xiao C, Gu P, Fan X. Repair of orbital bone defects in canines using grafts of enriched autologous bone marrow stromal cells. J Transl Med. 2014;12(1):123. https://doi.org/10.1186/1479-5876-12-123
  107. Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK). Eur J Hum Genet. 2013;21(10):1049-1053. https://doi.org/10.1038/ejhg.2012.301
  108. Lardenois A, Jagot S, Lagarrigue M, Guevel B, Ledevin M, Larcher T, Dubreil L, Pineau C, Rouger K, Guevel L. Quantitative proteome profiling of dystrophic dog skeletal muscle reveals a stabilized muscular architecture and protection against oxidative stress after systemic delivery of MuStem cells. Proteomics. 2016;16(14):2028-2042. https://doi.org/10.1002/pmic.201600002
  109. Rouger K, Larcher T, Dubreil L, Deschamps JY, Le Guiner C, Jouvion G, Delorme B, Lieubeau B, Carlus M, Fornasari B, Theret M, Orlando P, Ledevin M, Zuber C, Leroux I, Deleau S, Guigand L, Testault I, Le Rumeur E, Fiszman M, Cherel Y. Systemic delivery of allogenic muscle stem cells induces long-term muscle repair and clinical efficacy in duchenne muscular dystrophy dogs. Am J Pathol. 2011;179(5):2501-2518. https://doi.org/10.1016/j.ajpath.2011.07.022
  110. Sampaolesi M, Blot S, D'Antona G, Granger N, Tonlorenzi R, Innocenzi A, Mognol P, Thibaud JL, Galvez BG, Barthelemy I, Perani L, Mantero S, Guttinger M, Pansarasa O, Rinaldi C, Cusella De Angelis MG, Torrente Y, Bordignon C, Bottinelli R, Cossu G. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature. 2006;444(7119):574-579. https://doi.org/10.1038/nature05282
  111. Brown SG, Harman RJ, Black LL. Adipose-derived stem cell therapy for severe muscle tears in working German shepherds: two case reports. Stem Cell Discovery. 2012;2:41-44. https://doi.org/10.4236/scd.2012.22007
  112. Gibson MA, Brown SG, Brown NO. Semitendinosus myopathy and treatment with adipose-derived stem cells in working German shepherd police dogs. Can Vet J. 2017;58(3):241-246.
  113. Lewis DD, Shelton GD, Piras A, Dee JF, Robins GM, Herron AJ, Fries C, Ginn PE, Hulse DA, Simpson DL, Allen DA. Gracilis or semitendinosus myopathy in 18 dogs. J Am Anim Hosp Assoc. 1997;33(2):177-188. https://doi.org/10.5326/15473317-33-2-177
  114. Cuervo B, Rubio M, Sopena J, Dominguez JM, Vilar J, Morales M, Cugat R, Carrillo JM. Hip osteoarthritis in dogs: a randomized study using mesenchymal stem cells from adipose tissue and plasma rich in growth factors. Int J Mol Sci. 2014;15(8):13437-13460. https://doi.org/10.3390/ijms150813437
  115. Vilar JM, Cuervo B, Rubio M, Sopena J, Dominguez JM, Santana A, Carrillo JM. Effect of intraarticular inoculation of mesenchymal stem cells in dogs with hip osteoarthritis by means of objective force platform gait analysis: concordance with numeric subjective scoring scales. BMC Vet Res. 2016;12(1):223. https://doi.org/10.1186/s12917-016-0852-z
  116. Black LL, Gaynor J, Adams C, Dhupa S, Sams AE, Taylor R, Harman S, Gingerich DA, Harman R. Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs. Vet Ther. 2008;9(3):192-200.
  117. Guercio A, Di Marco P, Casella S, Cannella V, Russotto L, Purpari G, Di Bella S, Piccione G. Production of canine mesenchymal stem cells from adipose tissue and their application in dogs with chronic osteoarthritis of the humeroradial joints. Cell Biol Int. 2012;36(2):189-194. https://doi.org/10.1042/CBI20110304
  118. Case JB, Palmer R, Valdes-Martinez A, Egger EL, Haussler KK. Gastrocnemius tendon strain in a dog treated with autologous mesenchymal stem cells and a custom orthosis. Vet Surg. 2013;42(4):355-360. https://doi.org/10.1111/j.1532-950X.2013.12007.x
  119. Pascual-Garrido C, Guilak F, Rai MF, Harris MD, Lopez MJ, Todhunter RJ, Clohisy JC. Canine hip dysplasia: a natural animal model for human developmental dysplasia of the hip. J Orthop Res. 2018;36(7):1807-1817. https://doi.org/10.1002/jor.23828
  120. Biller B. Metronomic chemotherapy in veterinary patients with cancer: rethinking the targets and strategies of chemotherapy. Vet Clin North Am Small Anim Pract. 2014;44(5):817-829. https://doi.org/10.1016/j.cvsm.2014.05.003
  121. Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, Blake J, Schwager C, Eckstein V, Ansorge W, Ho AD. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol. 2005;33(11):1402-1416. https://doi.org/10.1016/j.exphem.2005.07.003
  122. Fritz V, Jorgensen C. Mesenchymal stem cells: an emerging tool for cancer targeting and therapy. Curr Stem Cell Res Ther. 2008;3(1):32-42. https://doi.org/10.2174/157488808783489462
  123. Kim SK, Kim SU, Park IH, Bang JH, Aboody KS, Wang KC, Cho BK, Kim M, Menon LG, Black PM, Carroll RS. Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin Cancer Res. 2006;12(18):5550-5556. https://doi.org/10.1158/1078-0432.ccr-05-2508
  124. Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 2002;62(13):3603-3608.
  125. Hwang Y, Kim D, Chang D, Ahn B, Kim YB, Kim G. Effects of neural stem cells and 5-fluorocytosine in canine metastatic lung tumor. J Vet Sci. 2017;18(2):257-260. https://doi.org/10.4142/jvs.2017.18.2.257
  126. Yi BR, Hwang KA, Kim YB, Kim SU, Choi KC. Effects of genetically engineered stem cells expressing cytosine deaminase and interferon-beta or carboxyl esterase on the growth of LNCaP rrostate cancer cells. Int J Mol Sci. 2012;13(10):12519-12532. https://doi.org/10.3390/ijms131012519
  127. Rici RE, Will SE, Luna AC, Melo LF, Santos AC, Rodrigues RF, Leandro RM, Maria DA. Combination therapy of canine osteosarcoma with canine bone marrow stem cells, bone morphogenetic protein and carboplatin in an in vivo model. Vet Comp Oncol. 2018;16(4):478-488. https://doi.org/10.1111/vco.12404
  128. Rout ED, Avery PR. Lymphoid neoplasia: correlations between morphology and flow cytometry. Vet Clin North Am Small Anim Pract. 2017;47(1):53-70. https://doi.org/10.1016/j.cvsm.2016.07.004
  129. Suter SE, Hamilton MJ, Sullivan EW, Venkataraman GM. Allogeneic hematopoietic cell transplantation in a dog with acute large granular lymphocytic leukemia. J Am Vet Med Assoc. 2015;246(9):994-997. https://doi.org/10.2460/javma.246.9.994
  130. Vail DM. Hematopoietic tumors. In: Ettinger SJ, Feldman EC, editors. Textbook of Veterinary Internal Medicine. 7th ed. Philadelphia: WB saunders; 2010, 2148-2163.
  131. Warry EE, Willcox JL, Suter SE. Autologous peripheral blood hematopoietic cell transplantation in dogs with T-cell lymphoma. J Vet Intern Med. 2014;28(2):529-537. https://doi.org/10.1111/jvim.12302
  132. Willcox JL, Pruitt A, Suter SE. Autologous peripheral blood hematopoietic cell transplantation in dogs with B-cell lymphoma. J Vet Intern Med. 2012;26(5):1155-1163. https://doi.org/10.1111/j.1939-1676.2012.00980.x
  133. Questions and Answers on Allogenic Stem Cell-Based Products for Veterinary Use: Specific Questions on Sterility [Internet]. London: European Medicines Agency; http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/06/WC500229927.pdf. Updated 2017. Accessed 2018 Sep 12.
  134. Cell-Based Products for Animal Use [Internet]. Rockville: Food and Drug Administration; https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM405679.pdf. Updated 2015. Accessed 2018 Sep 12.
  135. Stem Cell-Based Products for Veterinary Use: Specific Questions on Target Animal Safety to be Addressed by ADVENT [Internet]. London: European Medicines Agency; http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500210915.pdf. Updated 2016. Accessed 2018 Sep 12.
  136. Guideline on Safety Assessment of Cell-Based Products for Animal Use [Internet]. Gimcheon: Animal and Plant Quarantine Agency; http://www.qia.go.kr/viewwebQiaCom.do?id=44816&type=2_14dwyp. Updated 2018. Accessed 2018 Sep 12.