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group showed a shorter time of reaction to therapy [78] Fibrocartilaginous embolic myelopathy hUCB-MSCs; percutaneous transplantation into parenchyma; 1.0 Ă— 106 cells 1 dog No At 12 weeks; locomotor functions improved following transplantation. [68] SCI, spinal cord injury; NIBM-MSC, neurogenically-induced bone marrow-derived mesenchymal stem cell; IV, intravenous; IA, intra-arterial; IT, intrathecal; AD-MSC, adipose tissue-derived mesenchymal stem cell; BM, bone-marrow; BM-MNC, bone marrow-derived mononuclear cell; BMSC, bone-marrow-derived mesenchymal stem cell; hUCB-MSC, human umbilical cord derived mesenchymal stem cell. Fibrocartilaginous embolism (FCE), which results from SCI, cause ischemic myelopathy in dogs [67]. One clinical trial utilized human umbilical cord (hUCB)-derived MSCs in an FCE-suspected dog [68]. hUCB-derived MSCs was transplanted 7 days after decompression surgery. As a result, locomotor functions improved following transplantation in this dog. Along with SCI, stem cell treatment is applied in other neurological disease cases due to its immunomodulatory capacity and the neuroprotective and regenerative effects of paracrine factors induced by stem cells [69-71]. Canine meningoencephalomyelitis of unknown origin (MUO) is an intracranial non-infectious inflammatory disease [72,73]. The exact pathogenesis is still unclear, and immunosuppressive drugs are widely used as treatment options [72,74]. Similar to canine MUO, human multiple sclerosis, also known as chronic autoimmune inflammatory disease, is induced by the attack of autoreactive T-cells [75]. The immunomodulatory capacity of MSCs was tested in an experimental rodent model of autoimmune encephalomyelitis, and beneficial effects were seen as a result [76,77]. One study was conducted in which dogs affected by MUO were given MSC treatment [78]. Autologous BMSCs were administered by intrathecal injection in conjunction with intravenous and intraarterial injection in the right carotid artery in 8 dogs. All dogs showed early improvement in their general and neurological conditions without complications. However, this study divided 8 dogs into 3 treatment groups with different stem cell administration protocols and had no control groups. Thus, the treatment effects of stem cells in canine MUO are still uncertain. Promising improvements have been made in numerous studies using canine experimental SCI models, and these early results have led to clinical trials of stem cell therapy for various neurologic disease, including SCI cases. Further studies with controlled conditions are needed to verify the efficacy of stem cell therapy in companion animals with neurological disease. STEM CELL TRIALS IN DERMATOLOGIC DISEASE Normal skin is constantly being renewed and maintaining homeostasis using a pool of ASCs [79]. The basic process of skin wound-healing can be classified into inflammatory, proliferative, and maturation phases. The proliferation and remodeling phases require the complex processes of re-epithelialization, angiogenesis, stem cell activation, extracellular matrix remodeling, and scar formation [80]. As previously described [81-83], MSCs transplantation have demonstrated the therapeutic effects in skin wounds and dermal regeneration [81-83]. One study demonstrated the topical injection of BMSCs in an experimentally induced skin wound canine model [83]. The researchers concluded that BMSCs migrated to the region of inflammation, resulting in rapid re-epithelialization, angiogenesis, and increased collagen deposition. Two clinical cases demonstrated application of stem cells in large skin wound (Table 3). Autologous AD-MSCs with platelet-rich plasm was applied in a dog with the large skin defects due to train accident [84]. This case report showed complete closure of the wound 3 months after the stem cell transplantation. Another study showed 2 dogs with chronic chemical burn injuries that were not resolved with conventional treatments (16 and 24-month history) [85]. Both dogs were treated with regenerative therapy using human MSCs with poly (vynil-alcohol) hydrogel membranes, and complete epithelialization was observed after 2 months. These 2 clinical cases only demonstrated individual cases without controls. However, considering the treatment results of these cases, it can be concluded with some certainty that regenerative therapy using stem cells improves the wound healing process. In addition to skin wound https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 6/22 Stem-cell therapy in dogs and cats repair, application of AD-MSCs in one dog with hepatocutaneous syndrome (HS) has been reported [86]. This dog showed a favorable response to stem cell treatment for a long time. HS induces superficial necrolytic dermatitis associated with livers disease [87], and MSCs were applied for dermal and hepatocyte regeneration [80,83,88]. MSCs exert their beneficial effects on the treatment of immune-mediated diseases by inhibiting the proliferation of T-cells, B-cells, and dendritic cells [76]. They also alter the maturation of antigen-presenting cells and the cytokine secretion [2]. Because of the immunomodulatory effects of the MSCs, clinical trials using MSCs in atopic dermatitis (AD) have been conducted in dogs [23]. In this study, autologous AD-
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