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https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 2/22 Stem-cell therapy in dogs and cats STEM CELL TRIALS IN CARDIOVASCULAR DISEASE Interestingly, stem cell therapy is an emerging potential therapeutic modality for cardiovascular disease [31]. Stem cells are commonly applied in myocardial infarction cases, because treatment is difficult and damaged cardiomyocytes are rarely regenerated [10]. Treatment protocols vary depending on the transplanted cell type, delivery method, time of administration and frequency [33]. Various types of stem cells have been used for cardiac therapy, including skeletal myoblasts, BMSCs, ESCs, endogenous cardiac stem cells (CSCs), AD-MSCs and even iPSCs generated from human hair follicle keratinocytes [37-39]. Among these, BMSCs have 2 advantages: lower immunogenicity compared to the other types of stem cells, and the action of paracrine growth factors [39]. It is demonstrated that preclinical studies have shown the ability of MSCs to attenuate cardiac remodeling, restore cardiac function, and regenerate damaged myocytes in acute and chronic canine models [40,41]. iPSCs generated from human hair follicle keratinocytes can differentiate into a cardiogenic lineage and function as a biological pacemaker, allowing for their potential application as a novel therapy for the advanced treatment of atrioventricular block [37]. Theoretically, autologous transplantation of CSCs is also possible. A previous study has demonstrated that attenuation of left ventricle remodeling causes less fibrosis in canine model of myocardial infarction after autologous CSCs intramyocardial injection [33]. The stem cell transplantation method is also important for enhancing therapeutic efficacy and safety. Previously, stem cells were introduced into cardiomyocytes by either direct intramyocardial (subendocardial or subepicardial) injection or intracoronary injection [42,43]. Direct intramyocardial injection has the advantages of providing precise targeting of cell delivery to the ischemic region and higher cell retention compared with intracoronary injection. However, direct injection may induce subsequent inflammation, which reduces the survival of engrafted cells [43,44]. Intracoronary injection presents a high risk of coronary https://vetsci.org https://doi.org/10.4142/jvs.2020.21.e42 3/22 Stem-cell therapy in dogs and cats ESCs ASCs iPSCs Blastocyst Stem cells from adult tissues Adult somatic cells Reprogramming Stem cells Organ forming cells Transplantation Expansion & differentiation Neural cells Muscle cells Cardiac cells Intestinal cells Liver cells Blood cells Osteocyte Fig. 1. Schemes of basic concept and procedures for stem cell transplantation. Stem cells can be classified into ESCs, ASCs and iPSCs based on their sources. Simply, stem cells are expanded to specific types of cells and transplanted into the body. ESC, embryonic stem cell; ASC, adult stem cell; iPSC, induced pluripotent stem cell. embolism and low stem cell retention. To overcome these disadvantages, other stem cell delivery methods have been developed and utilized. Ultrasound-mediated microbubble destruction induced by micropump in intracoronary injection increases the vascular permeability, which enhances the homing of BMSCs into cardiomyocytes and increases cardiac function [44]. Another study introduced percutaneous retrograde coronary injection in combination with basic fibroblast growth factor (bFGF) [43]. Combination with bFGF enhances the efficacy of BMSCs by increasing the migration and viability of MSCs and promoting their differentiation into the cardiomyocyte phenotype. Only 2 studies have described cell-based treatment in veterinary clinical cardiac disease (Table 1). One study used allogeneic cardiosphere-derived cells in 5 dilated cardiomyopathy (DCM) dogs [45]. The beneficial effects of stem cell application were not detected in dogs with DCM during a 1-year follow-up. Another study transplanted allogeneic puppy deciduous teeth stem cells for the treatment of degenerative valvular heart disease [46]. The efficacy of treatment was evaluated for 2 months and resulted in improved heart function with alleviated clinical signs of heart failure. Because myocardial infarction is rare in dogs and cats [47], all of these implications of stem cell therapy for the resolution of cardiomyocyte damage are limited by the experiments due to the use of small and no-randomized samples. Although few pilot studies provide alternative treatment options for cardiovascular disease in veterinary clinics, further research and clinical trials are needed to evaluate the short- and long-term efficacy and complications of stem-cell treatment. STEM CELL TRIALS IN NEUROLOGIC DISEASE Spinal cord injury (SCI) causes temporary or permanent neurological defect in humans and companion animals [32]. Because SCI is a devastating condition in humans, several therapeutic experiments using canine SCI models and clinical trials with natural spinal cord-injured dogs have been conducted as preclinical trials [27,32]. Most of the injuries were induced by balloon catheter compression methods between T13 and L3 [48-55]. Few studies have used unilateral spinal cord hemisection between T11 and L2 [56,57]. Stem cells from either canine or human origin were used, most being allogeneic canine MSCs [51-55]. The
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