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administered systemic autologous or allogeneic feline AD-MSCs in refractory feline chronic gingivostomatitis (FCGS) [102,103]. https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 8/22 Stem-cell therapy in dogs and cats Table 4. Veterinary clinical stem cell trials in gastrointestinal disease Disease Cell therapy No. of dogs Control Evaluation periods/effects Ref. Inflammatory bowel disease Allogeneic adipose-derived MSCs; IV; 2 × 107 cells/kg 11 dogs in stem cell group No At 6 weeks; the dogs were well tolerated and given clinical benefits. [95,96] At pre-treatment and between 90 and 120 days post-treatment; endoscopic remission in 4 dogs and histological remission was not achieved Anal furunculosis hESC-derived MSCs; intra-lesional injection within the dermis and subcutaneous tissue around the perianal fistulas; 2 × 107 cells 6 dogs in stem cell group No At 7, 30, 60, 90, 180 days; the safety and therapeutic potential of hESC-MSCs were revealed. [100] FCGS Allogeneic AD-fMSCs; IV; 20 × 106 cells, 2 times, 1 month apart 7 cats in stem cell group No At 1 month, 3 months, and 6 months; clinical improvement and resolution in 4/7 cats; cured ~12–20 months [102] FCGS Autologous AD-fMSCs; IV; 20 × 106 cells, 2 times, 1 month apart 7 cats in stem cell group No At 1 month, 3 months, and 6 months; clinical improvement and resolution in 5/7 cats; cured ~3–9 months [103] Feline chronic enteropathy Allogeneic AD-fMSCs; IV; 2 × 106 cells/kg, 2 times, 2 weeks apart 7 cats in stem cell group; 4 cats in control group Yes At 2 weeks and 1 to 2 months; significant improvement or complete resolution of clinical signs in 5/7 cats [101] hESC, human embryonic stem cell; FCGS, feline chronic gingivostomatitis; MSC, mesenchymal stem cell; IV, intravenous; AD-fMSC, adipose tissue-derived feline mesenchymal stem cells. FCGS is a chronic inflammation of the oral mucosa and is associated with a highly reactive immune system [104]. These data support the clinical evidence of immunomodulatory effects of MSCs therapy. To date, compared with autologous MSCs, allogeneic MSCs have shown lower treatment efficacy and delayed clinical response. In the treatment of refractory GI disease, stem cell transplantations have been actively studied in both human and veterinary medicine. More specified studies on stem cell sources and treatment protocols for each disease may enable innovative clinical applications of stem cells in refractory chronic GI disease in the near future. STEM CELL TRIALS IN MUSCULOSKELETAL DISEASE Musculoskeletal disease includes injuries or pain of the joints and tendons, ligaments, muscles, nerves, and accompanying structures, which affect the ability to move. BMSCs are the progenitors for many mesenchymal tissues, such as bone, cartilage and fat [105]. Stem cell-based bone regeneration was evaluated using canine models. Bone defects were induced by surgery and reconstructed using allogeneic mandibular scaffold-loaded and autologous MSCs [105] or β-tricalcium phosphate and autologous BMSCs via the custom-made stem cellscaffold device [106]. Both studies demonstrated that the use of MSCs accelerated new bone formation in the mandibular or orbital defects, most likely due to increases in the absorption of bone grafts and osteogenesis. Stem cells are also used in muscle diseases. Duchenne muscular dystrophy is a devastating genetic disorder that induces severe muscle weakness and atrophy in humans [107]. To evaluate therapeutic stem cell efficacy in this incurable form of muscular dystrophy, golden retriever muscular dystrophy (GRMD) dogs were observed clinically as animal models for humans [108-110]. Intra-arterially delivered muscle stem cell [58,95] or mesoangioblasts (vessel-associated stem cells) [110] showed limitations in muscle damage with myofiber regeneration, dystrophin recovery and increased regeneration activity. Thus, these studies concluded that stem cells can provide clinical benefits in GRMD dogs. Few clinical trials related to muscle diseases have been reported [111,112]. Adipose-derived stem cells were injected into 2 dogs with severe skeletal muscle injuries. Clinical improvements and reductions in lesion size were observed after stem cell administration [111]. Semitendinosus myopathy is a rare muscular disorder in certain large breed dogs, and its exact etiology and pathogenesis are still unknown [112]. Because this muscle is responsible for non-weightbearing positional extension (hip, stifle, and tarsus) and flexion (stifle), lameness and pain are common clinical signs [113]. AD-MSCs treatment of these dogs improved clinical signs without recurrence of lameness, likely due to the prevention of the progression of fibrosis and muscle contracture in semitendinosus myopathy. Several experimental strategies have provided insight as to whether AD-MSCs therapy can be utilized for the regeneration and maintenance of articular cartilage in osteoarthritis [25,26,114,115]. Administration of autologous AD-MSCs stimulates extracellular matrix synthesis and chondrocyte proliferation and inhibits inflammatory reaction of cartilage [26,114]. In addition, growth factors contained in platelet-rich plasma and hyaluronic acid act as mediators, and potentiators, of the effect of MSCs [26,114]. Significant improvements in limb function, lameness, and
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