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transplantation time and dose after injury varied, and a small number of dogs (under 10 dogs in each group) were treated. Although these limitations make the efficacy of stem cell therapy inconclusive, several studies have shown promising improvements in functional outcomes and have proven a greater clinical benefit for stem cell therapy in comparison with the traditional treatment. https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 4/22 Stem-cell therapy in dogs and cats Table 1. Veterinary clinical stem cell trials in cardiovascular disease Disease Cell therapy No. of dogs Control Evaluation periods/effects Ref. Dilated cardiomyopathy Allogeneic cardiosphere-derived cells; intra-coronary artery (20 × 106 cells at left main artery and 10 × 106 cells at right coronary artery) 5 dogs in stem cell group Yes At day 1, 1, 2, 6, 12 months; No adverse events and no significant effects occurred during and after cell infusion. [45] Degenerative valvular heart disease Allogeneic puppy deciduous teeth stem cells; intravenous; 1 × 106 cells 2 times with 14-day interval 10 dogs in stem cell group (combination with stem cell therapy and standard treatment); 10 dogs in control group (only standard treatment) Yes At 30 and 60 days; left ventricular ejection fraction and quality of life scores were improved in study group. [46] Along with the experimental research, 9 studies evaluated the efficacy of the stem cell treatment in veterinary SCI clinical cases [58-66] (Table 2). Acute and chronic clinical spinal cord-injured dogs were treated with various stem cell protocols. Most of the trials used autologous BMSCs, one study used allogeneic AD-MSCs [63], and 2 other studies used olfactory mucosal or glial cells [60,61]. Seven studies concluded that stem cell transplantation was beneficial and improved locomotor function; however, most of the studies involved a small number of dogs, and only 3 studies include control groups. Two studies failed to show the distinct clinical beneficial effects of stem cell treatment [60,64]; however, they also concluded that stem cell treatment was safe, and there may be some beneficial effects of stem cell therapy in companion animals with SCI. https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 5/22 Stem-cell therapy in dogs and cats Table 2. Veterinary clinical stem cell trials in neurologic disease Disease Cell therapy No. of dogs Control Evaluation periods/effects Ref. SCI (T3-L7) Autologous NIBM-MSCs; intra spinal injection; 5.0 × 106 cells for 2 times with a 21-day interval. 13 dogs in stem cell group No At 2, 5, 7, and 12 months; improvement in gait score in 6 of the cases, and improvement in proprioception and nociception in 2 cases [58] SCI Autologous NIBM-MSCs; intra spinal injection; 5.0 × 106 cells 2 times with a 21-day interval. 7 dogs in stem cell group No At 2, 4 and 8 months; some beneficial effect of intraspinal injection of autologous NIBM-MSCs in dogs with paraplegia [59] SCI (T10-L4) Autologous olfactory mucosal cells; intraspinal transplant; 6.24 × 106 cells 23 in stem cell group; 11 in control group (received cell transport medium alone) Yes At 1, 3 and 6 months; no evidence for concomitant improvement in long tract function [60] Severe SCI (T11-L2) Autologous olfactory glial cells; intraspinal transplant; 5 × 104 cells 8 dogs in stem cell group No From 2 months to 1 year; the transplantation procedure itself is noninjurious and feasible; beneficial effect on locomotion [61] SCI Allogenic AD-MSCs; intra spinal injection; 1 × 107 cells 9 dogs in surgery and stem cell group; 25 dogs in surgery group Yes Follow-up more than 6 months; better recovery outcomes compared to decompression surgery alone [62] Severe acute SCI (T6-L5) Autologous BM stromal cells; IT into the CSF; 1.0 × 106 cells to 6 × 106 cells (mean, 3 × 106 cells) 3 times at 1-week intervals 7 dogs in stem cell group No Follow-up until 29-62 months after SCI; there were no complications; Only 2 of 7 dogs regained the ability to walk, no changes in sensory function [63] SCI (T13-L7) Autologous BMSCs; intraspinal transplant (intraparenchymal); 1 × 106 cells in each 1 cm3 of lesion 4 dogs in stem cell group No At 100 days, 12 months and 18 months; faster clinical recovery and improved movement in 3 of the 4 dogs; no changes in magnetic resonance imaging [65] Severe SCI (T11-L4) Autologous BM-MNCs; subarachnodal to the lesioned spinal cord; 4.5 × 106 to 2.3 × 109 cells (mean, 8.88 × 107 cells) 36 dogs in stem cell group; 46 dogs in control group Yes Ambulatory recovery rate was assessed (mean time of ambulatory recovery was 34.84 days); significant increase in the recovery rate was revealed [66] Chronic SCI Autologous BMSCs; IT into the cerebrospinal fluid; 0.3 × 105 cells to 3 × 106 cells (median, 1.3 × 106 cells) 3 times at 1-week intervals 10 dogs in stem cell group; 13 dogs in control group Yes At 1, 2, 3, 4, 5, and 6 months, until 6-35 months; there were no complications; improvement of pelvic limb locomotor function [64] Meningoencephalomyelitis of unknown origin Autologous BMSCs; IT in the cisterna magna (2.0 × 106 cells), IV (0.5 × 106 cells), and IA in the right carotid artery (4.0 × 106 cells) 8 dogs in stem cell group (3 in IT + IA, 4 in IT + IV, 1 in IT + IA after IT + IV) No For 6 months up to 2-year follow-up; No major short- or long-term adverse effects; early improvement in general and neurological conditions, IT + IA
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