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MSCs were intravenously administrated to 5 dogs with AD. No specific adverse effects were observed, but they failed to improve clinical signs. Because of the repairing and regenerative capabilities of stem cells, most research has focused on clinical therapeutic applications of stem cells for damaged tissues and skin repair [3]. Recently, the application of stem cells has extended to incurable and recurrent immunemediated skin diseases that have not responded to the conventional treatment. However, there is a lack of research on appropriate cell sources, mechanisms of action, efficacy, and safety of clinical trials in veterinary medicine. STEM CELL TRIALS IN GASTROINTESTINAL (GI) DISEASE The management of GI diseases is often challenging because of the complex pathogenesis, morphology and function of the GI system [89]. Various pathogeneses include infection, inflammation, neoplasm, and functional disturbance. Stem cell therapy may play an important role in human GI disease. Ongoing clinical trials with stem cells have been reported in disease that are difficult to treat, such as cirrhosis and liver failure, inflammatory bowel disease (IBD), and pancreatitis [89-91]. Many preclinical studies have shown promising results in human medicine, and these clinical approaches have also been tested in veterinary medicine. The effects of autologous BMSCs and AD-MSCs were investigated in formocresol-induced oral ulcers in dogs [92,93]. Both studies demonstrated the rapid healing of induced oral ulcer following stem cell therapy compared with other treatments or control groups. This was most likely accomplished through angiogenesis and epithelial/connective tissue proliferation. The gene expression levels of angiogenesis and epithelial/connective tissue markers such as vascular https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 7/22 Stem-cell therapy in dogs and cats Table 3. Veterinary clinical stem cell trials in dermatologic disease Disease Cell therapy No. of dogs Control Evaluation periods/effects Ref. Skin wound (trauma) Autologous adipose derived MSCs + platelet-rich plasma; spraying the cells over the wound surface (5 applications at day 11, 17, 23, 31, 41) 1 dog No A complete closure of the wound occurred 3 months after the start of the regenerative therapy [84] Chronic skin wound Human MSCs + poly (vynil-alcohol) hydrogel membranes; locally infiltrated; 1 × 105 cells/cm2 2 dogs No A complete epithelialisation was observed after 2 months [85] Hepatocutaneous syndrome Allogenic adipose-derived MSCs; IV and intrahepatic injection; 5 × 107 cells for 46 times 1 dog No Follow-up for 32 months; stem cell therapy may extend a patient's survival time. [86] AD Autologous adipose-derived MSCs; intravenous route; 1.3 × 106 cells/kg 5 dogs in stem cell group No At 2–3, 6–8, 10–12 weeks; the results were safe but not effective for controlling clinical signs and pruritus induced by AD. [23] AD, atopic dermatitis; MSC, mesenchymal stem cell; IV, intravenous. endothelial growth factor (VEGF) and collagen [93], VEGF, collagen, platelets-derived growth factor and epidermal growth factor [92] were significantly higher in the MSC-treated group. IBD is a multifactorial, idiopathic infiltration of inflammatory cells in the small and large intestines. Lymphocytic-plasmacytic colitis is the most common form in dogs and has several histopathologic and molecular features that resemble human IBD [90,94]. The efficacy of a single intravenous injection of allogeneic AD-MSCs was evaluated in 11 dogs with IBD [95,96]. While the dogs were partially tolerant to conventional therapy, MSCs transplantation improved clinical scores, serum albumin, and serum biomarkers (folate and cobalamin) when compared to baseline [96]. Further evaluation with endoscopic and histological scales showed improved macroscopic changes (endoscopic index), but no improved microscopic histological scores [95]. Although the small sample size and absence of a control group or qualified evaluation methods may obscure the real effects of MSCs, these data provide a short-term safety and therapeutic potentials of allogeneic MSCs in dogs with IBD. Canine anal furunculosis (CAF) is a chronic, immune-mediated disease in dogs characterized by the occurrence of perianal fistulas that resemble fistulizing Crohn's disease (one type of IBD) in humans [90,97]. Over 80% of CAF is diagnosed in middle-to-old-aged German shepherd dogs, but the pathogenesis of CAF, except for the genetic causes, is not fully understood [98,99]. Long-term immunosuppressive drugs are the most effective therapy, but relapses and refractory cases are common [97]. The efficacy of intralesional injection of human ESC (hESC)-derived MSCs in 6 dogs with refractory CAF was evaluated [100]. The hESC-MSCs were well-tolerated, and all 6 dogs were free of fistulas at 3 months postinjection. However, 2 of the 6 dogs experienced recurrence of fistulas by 6 months, indicating that multiple injection may be required in some cases. There were only 3 feline stem cell studies in GI disease (Table 4). One feline study was conducted on chronic enteritis (lymphocytic-plasmocytic enteritis) [101]. Allogeneic feline AD-MSCs were administered, and clinical improvements were observed compared with the placebo at the 2-month follow-up. Two other studies
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