Stem cells offer a...

Stem cell research acquired great attention during last decade inspite of incredible therapeutic potential of these cells the ethical controversies exists. Stem cells have enormous uses in animal cloning, drug discovery, gene targeting, transgenic production and regenerative therapy. Stem cells are the naive cells of body which can self-renew and differentiate into other cell types to carry out multiple functions, these properties have been utilized in therapeutic application of stem cells in human and veterinary medicine. The application of stem cells in human medicine is well established and it is commonly used for chronic and accidental injuries. In Veterinary sciences previous studies mostly focused on establishing protocols for isolation and their characterization but with advancement in array of techniques for in vitro studies, stem cells rapidly became a viable tool for regenerative therapy of chronic, debilitating and various unresponsive clinical diseases and disorders. Multipotent adult stem cells have certain advantages over embryonic stem cells like easy isolation and expansion from numerous sources, less immunogenicity and no risk of teratoma formation hence their use is preferred in therapeutics. Adult stem cells have been utilized for treatment of spinal injuries, tendonitis, cartilage defects, osteoarthritis and ligament defects, liver diseases, wounds, cardiac and bone defects in animals. The multi-potential capability of these cells can be better utilized in near future to overcome the challenges faced by the clinicians. This review will emphasize on the therapeutic utilization and success of stem cell therapies in animals.


Introduction
field of stem cell research.Stem cells retain the ability to become some or all of the more than 200 different Stem cells offer an unprecedented hope in cell types in the body hence, unique regenerative treating many debilitating diseases of humans as well potential of these cells make their use indispensible in as animals.They have two important distinguishing the area of therapeutics.Stem cells are undoubtedly, characteristics, first they are unspecialized cells most promising for cell-based therapies that are capable of self-renewal through cell division, currently tested in pre-clinical trials for a wide range of sometimes after long periods of inactivity and second, ailments for their therapeutic potential.The basic under certain physiologic or culture conditions, they mechanism of action and generalized applications of can be differentiated to tissue-or organ-specific cells mesenchymal stem cells were reviewed by various with special functions.Stem cells can be classified as researchers [5,6].Most of the reports mainly focused adult and embryonic stem cells; adult stem cells are on orthopedic injuries of horses which exist as a big derived from adult body organs whereas embryonic challenge ahead of clinicians [7,8].The current stem cells from embryo.In adults, stem cells act as a compilation emphasizes on the preclinical and clinical repair system by replenishing tissues of the body studies of the utilization of embryonic and adult stem whereas in embryonic stem cells differentiate into all cells in laboratory animals, pets and farm animals.The the specialized cells and develop into adult.[10,11] successful allogenic stem cell graft in humans using was followed by isolation and characterization of ES donor bone marrow was undertaken in the United cells in other species like hamster, mink, rabbit, rat, States of America [50,51].Currently, there are many monkey, marmoset, chicken, human, baboon, dog, cat, research groups studying in vitro expansion of these horse, pig, cow, sheep, goat and buffalo [12][13][14][15][16][17][18][19][20][21][22][23].Adult and other stem cells for direct clinical applications stem cells are of various types, hemopoeitic stem cells, [52].Stem cells must be characterized according to mesenchymal stem cells, neural stem cells, skin stem criteria decided by International Society for Cell cells, retinal stem cells etc. [24].Mesenchymal Stem Therapy (ISCT) before they are utilization for therapy Cells (MSCs) can be isolated from bone marrow, fat, [53].In animals, MSCs derived either from bone umbilical cord blood (UCB), amniotic fluid, placenta, marrow or adipose tissues for their routine use in dental pulp, tendons, synovial membrane and skeletal experimental studies and clinical cases [54,47].MSCs muscle [25][26][27][28][29][30][31][32][33].They have the potential to differenare beneficial in handling various chronic and tiate into cells of various tissues like fibroblasts, debilitating clinical conditions of canines, equines and muscle, bone, tendon, ligament, and adipose tissue caprines though there are very limited reports in large [34,35,36,37].Friedenstein and co-workers [25] ruminants on therapeutic application of stem cells isolated these cells as colony-forming unit fibroblasts research is still going.Many private companies like from murine bone marrow.Further, Caplan (1991) for Vetstem (U.S.A., http://www.vet-stem.com/),Medistem the first time named these cells as mesenchymal stem Inc. (U.S.A., http://medisteminc.com/),Histostem cells.MSCs have been isolated from a number of (South Korea, http://www.histostem.co.kr) provide species like human, rat, mice, dog, cat, pig, horse, stem cell therapy for animals and claims cure for sheep, goat, cattle [11,[38][39][40][41][42][43][44][45][46].MSCs can be isolated orthopedic and other injuries (for websites see reference).Recently, some institutions like North Cardiac defects Carolina state university, Cambridge university were Laflamme and co-workers [64] injected diffin news for treatment of canine spinal injuries.erentiated cardiac-enriched hESC progeny into the left ventricular wall of athymic rats and found that grafts

Spinal injuries
consisted predominantly of cardiomyocytes by 4 The remarkable developmental potential and weeks.hESCs can form human myocardium in the rat replicative capacity of human embryonic stem (ES) heart, permitting studies of human myocardial cells were utilized by transplanting neural precursors development and physiology and supporting the into the brain of immunosuppressed neonatal mice and feasibility of their use in myocardial repair.Mouse ES no teratomas emerged within 8 weeks after implanderived cardiomyocytes were engrafted in injured tation [55].In similar way neural progenitor population myocardium of rat this resulted in an angiogenetic of cells was used in the successful treatment of a effect, and subsequently improved cardiac function Parkinson's rat model for 12 weeks with no teratoma during the 32-week observation period [65].Menard formation [56].hESC derived neurons were injected and associates [66] transplanted murine ES derived in primate and rodent models for treatment of neuronal cardiomyocytes in 18 sheep in which myocardial injuries without tumor formation [57].Acute spinal infarction was induced they found that ESCs were injuries are common in canines and felines that lead to colonized in the scar area and accompanied by a loss of tissue, including myelinated fibre tracts functional bene?t of the damaged myocardium.The responsible for carrying nerve impulses.The nervous findings obtained in a clinically relevant large-animal tissue has limited regeneration capacity and complete model of heart failure strengthen the potential restoration of locomotor activity is challenge to therapeutic use of ESC to regenerate the severely modern therapeutics.Therefore transplantation of dysfunctional myocardium and bring additional stem cells with the ability to differentiate into neurons evidence for an immune privilege of these cells.and supporting cells may be a practical method for Cartilage defects recovery.The differentiation potential of stem cells was assessed and they not only they differentiated but Mouse ES cells (AB2.2 or CCE cells) were also integrated into axonal pathways and thus aid in transplanted into articular cartilage defects in the regeneration of injured nerves [58].Xenogenic patellar groove of immunosuppressed rats and cells transplantation of human UCB stem cells in rats were observed 8 weeks after transplantation.Cells following spinal cord injury significantly enhanced produced cartilage resulting in repair of defect this locomotor function within 14 days after therapy as indicated environment of osteochondral defects is compared to the control group [58].Bone marrow chondrogenic for ES cells [67], where as another derived MSCs were first used in Rhesus monkeys for group created full-thickness osteochondral defects on nervous tissue regeneration which appeared the patella groove of SD rats, and treated these rats promising [59].Intrathecal implantation of autologus with ES cells embedded in collagen gel.Thirty-five bone marrow derived MSCs improved locomotor ES-like colonies from 40 IVP sheep embryos, positive activity significantly in six dogs within one week [60].for stage-specific embryonic antigens (SSEAs), were Similarly allogenic UCB derived MSC transplantation pooled in groups of two or three, embedded in fibrin resulted in nerve regeneration in canine fetuses.In glue and transplanted into osteochondral defects in the UCB-MSC treated group animals the gait was medial femoral condyles of 14 ewes [68].Sheep ESimproved in 2 weeks and the weight bearing power of like cells transplanted into cartilage defects stimulate the pelvic limbs was also improved.The improved the repair process to promote better organization and nerve conduction velocity and distinct structural tissue bulk.The utilization of MSCs for the repair of consistency of the nerve cell bodies was observed in cartilaginous tissue that is difficult to heal in adult lesions treated with MSCs [61].Encouraging results animals.MSCs can differentiate into chondrogenic were reported by same group in which adipose derived lineage [69] and utilized to treat cartilage defects.The stem cells (ADSCs) were used to treat spinal injury in articular cartilage defects were treated with MSCs canine [62].The comparison of autologous and with polymers [70], type I collagen [71], and polylactic allogenic transplantation of canine bone-marrow acid [72].Infrapatellar fat pad derived mesenchymal derived MSCs in experimentally-induced spinal cord stem cells were used in rabbits for treatment of injury (SCI) revealed that both approaches could be osteoarthritis [73].Caprine osteoarthritis model utilized clinically [63].
showed local delivery of adult mesenchymal stem cells to injured joints stimulates regeneration of adult New Zealand White rabbits, treated group shows meniscal tissue and retards the progressive destruction significant improvement in its biomechanical [74].Chronic osteoarthritis in 21 dogs was treated properties after 4 weeks .Delivery of bone marrow expression [81].In race horses, the adipose derived concentrate to acute full-thickness cartilage defects MSCs were used to successfully treat experimental has the clinical potential to improve cartilage healing tendinitis [47]. in equine model [54].MSC therapy provides a simple, Ligament healing can be enhance by transplanarthroscopically applicable, and clinically effective tation of mesenchymal stem cells (MSCs), which are approach for cartilage repair.
demonstrated to differentiate into fibroblast-like cells in ligament injury sites in rats and survive upto 28 days Tendon and ligament repair [82].Equine suspensory ligament injuries are The mechanical properties of healing tendons challenging because healing process is slow and reand ligaments are not comparable to those of normal injuries are common.The bone marrow components tissue, the quality of the tendon and ligament healing were injected for recovery from ligament injuries in can be improved with altered therapeutic strategies 100 horses and found effective [83].Therapeutic which include stem cell therapy.Bone marrow derived application of adult stem cells in equine tendonoautologous MSCs along with collagen gel were used to pathies and orthopedics is well studied and many repair surgically induced patellar tendon defect in reports are available on their clinical use [7,8].

Bone Repair
incisional wound healing and tissue regeneration in rabbit and fetal sheep [96,97].In caprine Wharton's The MSCs can undergo osteogenic differenjelly mesenchymal stem cells (WJMSCs) of umbilical tiation, and exploration of the potential for using cord were used to treat cutaneous wounds in goat.autologous stem cell therapy to augment bone repair Results showed complete re-epithelialization at day 7 and regeneration is well reported.MSCs stimulates of in treated group with less inflammation, thinner new bone formation in areas of implant site, indicating granulation tissue formation with minimum scar [48].that either these cells were infiltrating the adjacent MSCs were also found useful for treating host bone or stimulating the host bone to regenerate cerebral infarction [98] and ischemia [99], myocardial new bone [84,85].The preclinical studies were carried infarction [100], autoimmune disorders [101] in out in laboratory animals like rat, rabbit.Canine experimental models.segmental bone defects were treated with autologous bone marrow derived MSCs loaded onto porous ceramic Conclusion cylinders.The results obtained were encouraging Stem cells are undoubtedly, most promising for showed significantly greater amount of bone as cell-based therapies thereby provides a powerful and compared to control [86].Further, non-union fracture flexible option for veterinarians to restore function and in dog was cured by autologous transplan-tation of improve animal health through the novel techniques.adipose derived MSCs with hydroxyapatite and In veterinary sciences, stem cells are mainly used for chitosan scaffold [87].In another study allogenic the treatment in canines and equines whereas research transplantation of canine MSCs proved worthy for is still going on in other farm animals.However their repair of critical sized segmental defects [88].
extensive use in all clinical condition cannot be Among large-sized animals the use of sheep recommended because of high treatment expenditure autologous BMSC in conjunction with hydroxyapatite yet, certain chronic and irreparable conditions can be ceramic (HAC)-based carriers results in faster bone better treated with these cells and the cost of repair compared to hydroxyapatite ceramic HAC production will hopefully be reduced when extent of alone [89].Goat Bone marrow derived MSCs cultured production is increased.Though stem cells have with scaffolds could repair the segmental bone defect immense potential in therapeutics their clinical use in tibia by 8 weeks after surgery [90].These reports requires extensive research for standardization of the demonstrate the feasibility and efficiency of using treatment protocols, routes and doses.Further, MSCs to augment the repair of bone defects in guidelines and regulations for the controlled use of animals.
stem cells in animals will become a near future need.

Wound Healing
The modern vets-scientist team efforts will play a pivotal role in the development and implementation of The effects of embryonic stem cells (ESCs) on these innovative strategies to ultimately improve diabetic wound healing were investigated using an livestock production and pet care.excisional skin wound model in 110 diabetes-induced rats.The topical ESCs injections enhanced diabetic References wound healing during the early stage, and suggested standard research databases like MEDLINE, AGORA Stem cells are valuable tools for gene targeting and Google Scholar search engine on internet were [1], cloning [2], chimera production [3] and transgenic used for collection of full papers and abstracts animals [4] which brought much excitement in the To cite this article: Gade NE, Pratheesh MD, Nath A, Dubey PK, Amarpal, Sharma GT (2012) Therapeutic potential of stem cells in veterinary practice, Vet World, 5(8): 499-507.doi: 10.5455/vetworld.2012.499-507however some papers were also collected from list of and cultured easily with high ex vivo expansion rate.references of other papers.This makes these cells an attractive tool in regenerative medicine for cell therapy [45].Sources of stem cells Stem cells in veterinary regenerative therapy Stem cells can be classified as Embryonic Stem Cells (ESCs) and Adult Stem Cells (ASCs) depending Stem cell therapy involves various routes for on their source (Figure-1).The plasticity is the ability transplantation of cells into patients like local delivery of stem cells to differentiate which may form one cell or systemic infusion.Stem cells can be derived from type or multiple types of cells (Figure-2).Totipotent same animal (autologous), same species (allogeneic) means ability to differentiate into all three germ layers or from different species (xenogenic) for transplanincluding placenta similarly pluripotent stem cells can tation.Recent studies report many interesting form all three germ layers except placenta.The examples of the therapeutic use of MSCs and ESCs multipotent stem cells can differentiate into multiple [47-49].Stem cells address a broad spectrum of cell types of particular tissue type whereas unipotent indications, including spinal cord injury, bone, can form only one cell type [9].The first successful cartilage and cardiovascular repair.In 1968, first report of mouse embryonic stem cells (ESCs) [78].Similar combination with autologous adipose derived MSCs and all treated was used for Achillies tendon repair in rabbit model animals showed improved gait[75].Canine[79].It was found that MSCs treated groups better mesenchymal stem cells (MSCs) seeded in type I regain the normal tendon maximum force, stress, collagen-glycosaminoglycan (CG) matrices were modulus, and strain energy density compared with used in 10 dogs for repair of cartilage defects of knee controls.In equine, autologous bone marrow derived joints[76].The treatment of cartilage defects is MSCs after in vitro expansion were utilized and found challenge to practitioners though polymer based effective for regeneration tendon matrix in superficial treatment is used it does not provide efficient cure.flexor tendon injury[80].The collagenase induced Another major obstacle to the application of MSCs in tendinitis in the superficial digital flexor tendon in 8 cartilage repair is improving the integration of horses was treated with adipose derived nucleated neocartilage matrix with the surrounding native cells (ADNC) injection.The treated group showed cartilage matrix.In large-animal models, sheep were improvement tendon organization which was assessed treated with in vitro differentiated MSCs for repair of by cartilage oligomeric matrix protein (COMP) chronic osteochondral[77] .P. and Thomson, J.A. (2003).Homologous that ESCs offers a novel therapeutic modality for the recombination in human embryonic stem cells.Nat.treatment of diabetic wounds [49].Krause and Biotechnol., 3:319-321.associates[91]found that adult bone marrow cells give 2. Stice, S.L. and Keefer, C.L. (1993).Multiple rise to epidermal keratinocytes, follicular epithelial generational bovine embryo cloning.Biol.Reprod., cells, sebaceous gland cells, dendritic cells after their 48: 715-719.transplantation in mice.Bone marrow derived 3. Piedrahita, J.A., Anderson, G.B. and BonDurant, R.H. mesenchymal stem cells were injected around wound (1990).On the isolation of embryonic stem cells: Comparative behavior of murine, porcine and ovine and their application to the wound bed in an excisional embryos.Theriogenology, 34: 879-901.wound model enhanced healing significantly in normal 4. Saito, M., Iwawaki, T., Taya, C., Yonekawa, H., and diabetic mice [92].Autologous bone marrow Noda, M., Inui, Y., Mekada, E., Kimata, Y., Tsuru, A. derived nucleated cells transplanted in experimental and Kohno, K. (2001).Diphtheria toxin receptorrabbits and clinical cases to evaluate their tissue mediated conditional and targeted cell ablation in regeneration potential in full thickness wounds [93], transgenic mice.Nat.Biotechnol., 19:746-750.burn wounds [94] and corneal alkali burn wounds 5. Ribitsch, I., Burk, J., Delling, U., Geibler, C., Gittel, [95].In xenogenic model human MSCs were used for C., Julke, H. and Brehm, W. (2010).Basic