Concise Review: Stem Cell Trials Using Companion Animal Disease Models.

Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more realistic animal models. In veterinary medicine, companion animals naturally develop many diseases that resemble human conditions, therefore, representing a novel source of preclinical models. To understand how companion animal disease models are being studied for this purpose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in dogs and cats, excluding laboratory animals, induced disease models, cancer, and case reports. Disease models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopathy, inflammatory bowel diseases, Crohn's fistulas, meningoencephalomyelitis (multiple sclerosis-like), keratoconjunctivitis sicca (Sjogren's syndrome-like), atopic dermatitis, and chronic (end-stage) kidney disease. Stem cells evaluated in these studies included mesenchymal stem-stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autologous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints and protocols were feasible, and the stem cell therapies were reportedly safe and elicited beneficial patient responses in all but two of the trials. In conclusion, companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. However, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models. Stem Cells 2016;34:1709-1729.

Rat models of cardiometabolic diseases: baseline clinical chemistries, and rationale for their use in examining air pollution health effects.

Individuals with cardiovascular and metabolic diseases (CVD) are shown to be more susceptible to adverse health effects of pollutants. Rodent models of CVD are used for examining susceptibility variations. CVD models developed by selective inbreeding are shown to represent the etiology of human disease and metabolic dysfunction. The goal of this article was to review the origin and the pathobiological features of rat models of varying CVD with or without metabolic syndrome and healthy laboratory rat strains to allow better interpretation of the data regarding their susceptibility to air pollutant exposures. Age-matched healthy Sprague-Dawley (SD), Wistar (WIS) and Wistar Kyoto (WKY), and CVD-prone spontaneously hypertensive (SH), Fawn-Hooded hypertensive (FHH), SH stroke-prone (SHSP), SHHF/Mcc heart failure obese (SHHF) and insulin-resistant JCR:LA-cp obese (JCR) rat models were considered for this study. The genetics and the underlying pathologies differ between these models. Normalized heart weights correlated with underlying cardiac disease while wide differences exist in the number of white blood cells and platelets within healthy strains and those with CVD. High plasma fibrinogen and low angiotensin converting enzyme activity in FHH might relate to kidney disease and associated hypertension. However, other obese strains with known kidney lesions do not exhibit decreases in ACE activity. The increased activated partial thromboplastin time only in SHSP correlates with their hemorrhagic stroke susceptibility. Increases plasma lipid peroxidation in JCR might reflect their susceptibility to acquire atherosclerosis. These underlying pathologies involving CVD and metabolic dysfunction are critical in interpretation of findings related to susceptibility variations of air pollution health effects.

Large Animal Models in Regenerative Medicine and Tissue Engineering: To Do or Not to Do.

Rapid developments in Regenerative Medicine and Tissue Engineering has witnessed an increasing drive toward clinical translation of breakthrough technologies. However, the progression of promising preclinical data to achieve successful clinical market authorisation remains a bottleneck. One hurdle for progress to the clinic is the transition from small animal research to advanced preclinical studies in large animals to test safety and efficacy of products. Notwithstanding this, to draw meaningful and reliable conclusions from animal experiments it is critical that the species and disease model of choice is relevant to answer the research question as well as the clinical problem. Selecting the most appropriate animal model requires in-depth knowledge of specific species and breeds to ascertain the adequacy of the model and outcome measures that closely mirror the clinical situation. Traditional reductionist approaches in animal experiments, which often do not sufficiently reflect the studied disease, are still the norm and can result in a disconnect in outcomes observed between animal studies and clinical trials. To address these concerns a reconsideration in approach will be required. This should include a stepwise approach using in vitro and ex vivo experiments as well as in silico modeling to minimize the need for in vivo studies for screening and early development studies, followed by large animal models which more closely resemble human disease. Naturally occurring, or spontaneous diseases in large animals remain a largely untapped resource, and given the similarities in pathophysiology to humans they not only allow for studying new treatment strategies but also disease etiology and prevention. Naturally occurring disease models, particularly for longer lived large animal species, allow for studying disorders at an age when the disease is most prevalent. As these diseases are usually also a concern in the chosen veterinary species they would be beneficiaries of newly developed therapies. Improved awareness of the progress in animal models is mutually beneficial for animals, researchers, human and veterinary patients. In this overview we describe advantages and disadvantages of various animal models including domesticated and companion animals used in regenerative medicine and tissue engineering to provide an informed choice of disease-relevant animal models.