Large animal models for stem cell therapy

Abstract

The field of regenerative medicine is approaching translation to clinical practice, and significant safety concerns and knowledge gaps have become clear as clinical practitioners are considering the potential risks and benefits of cell-based therapy. It is necessary to understand the full spectrum of stem cell actions and preclinical evidence for safety and therapeutic efficacy. The role of animal models for gaining this information has increased substantially. There is an urgent need for novel animal models to expand the range of current studies, most of which have been conducted in rodents. Extant models are providing important information but have limitations for a variety of disease categories and can have different size and physiology relative to humans. These differences can preclude the ability to reproduce the results of animal-based preclinical studies in human trials. Larger animal species, such as rabbits, dogs, pigs, sheep, goats, and non-human primates, are better predictors of responses in humans than are rodents, but in each case it will be necessary to choose the best model for a specific application. There is a wide spectrum of potential stem cell-based products that can be used for regenerative medicine, including embryonic and induced pluripotent stem cells, somatic stem cells, and differentiated cellular progeny. The state of knowledge and availability of these cells from large animals vary among species. In most cases, significant effort is required for establishing and characterizing cell lines, comparing behavior to human analogs, and testing potential applications. Stem cell-based therapies present significant safety challenges, which cannot be addressed by traditional procedures and require the development of new protocols and test systems, for which the rigorous use of larger animal species more closely resembling human behavior will be required. In this article, we discuss the current status and challenges of and several major directions for the future development of large animal models to facilitate advances in stem cell-based regenerative medicine.

Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

“…Due to similarities in heart rate, anatomical and physiological parameters, large animal models have been advocated as superior to rodents in their ability to predict the results of clinical studies in cardiac regeneration [11, 12]. To our knowledge, however, there is no conclusive evidence supporting the contention that large animal models are superior to rodents – particularly mice – for efficacy testing of cardiac stem cell therapies.…”

“…However, the ability of small rodents - particularly the mouse model - to predict the results of human stem cell-based myocardial regenerative trials has been vigorously challenged [11]. This assumption is based on the premise that the anatomical and physiological differences between mice and humans are sufficient to lead to variant results between preclinical models and clinical trials.…”

“…Clinical translation of these highly advanced cell products requires new methods for appropriate safety and efficacy testing with regard to application in patients. The role of animal models to meet these requirements and ensure a full understanding of the biology of stem cell-based therapies is substantially and continually increasing [11]. …”

Proresolving Nanomedicines Activate Bone Regeneration in Periodontitis

“…humans than other commonly used laboratory animals in anatomy, physiology, immunology, and oral structures and is specifically suitable for regenerative studies (Harding et al 2013). For these reasons, it is widely used in cardiovascular, digestive tract, and skin studies (Forster et al 2010).…”

Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency

“…However, concerns exist about whether iPSCs, in particular, have full pluripotent potential and whether they are safe to be applied to transplantation therapy. Moreover, there is growing recognition that animal models other than rodents are needed for many biomedical applications (1,2), including the development of procedures for establishing xenografts from whole organs and transplanted cells. Moreover, rodents are not always appropriate for mimicking some human genetic and infectious disease states, and, for some surgical and clinical monitoring purposes, rodents are simply too small to be practical (3,4).…”