Mice have been a species of choice to study stem cell biology in mammals. They are relatively inexpensive, reproduce quickly, and can be easily manipulated genetically. However, the ability of mouse experiments to predict the effectiveness of stem cell-based therapy remains controversial. The failure of many mouse models to precisely recapitulate particular human disease phenotypes has compelled investigators to examine animal species that may be more predictive of humans. Larger animals, such as rabbits, dogs, pigs, goats, sheep, and non-human primates, are often better models than mice for this purpose. They have a longer life span, which facilitates longitudinal studies critical for most stem cell applications. Many physiological parameters (for example, immune system properties that play an important role in the reaction of the host animal to cell transplantation) are much closer to humans than are those of rodents. Large animals also have significant advantages regarding the number and types of stem cells that can be reproducibly extracted from a single animal and manipulated in sufficient quantity for analysis and for various applications.

Large animal species can provide significant advantages when modeling specific human disease conditions and testing stem cell therapies. The following are several examples. Non-human primates and humans have very similar central nervous systems. Non-human primates can recapitulate human pathology and behavior in experimental models of a variety of neurological diseases, making them the most suitable species for testing stem cell therapies for brain diseases . Several issues in the use of monkeys, such as the cost of husbandry and the specialized care that can be required for long-term monitoring, should be considered. Along with cat, dog, and non-human primate models, pigs are becoming very attractive as models to test stem cells for treating spinal cord injury. Advances in experimental surgery allow the creation of consistent and predictable deficits after calibrated spinal trauma very similar to human pathology. Another advantage is the ability to use equipment and techniques developed for human applications for cell delivery and monitoring of the animal. Serious limitations in understanding the specifics of spinal cord injury and recovery were discovered recently in rat models . Clearly, interpretation of the results of intervention and attempts to extrapolate the conclusions to human trials will be extremely difficult if based solely on experiments in the rat model. Another example of limitations of rodent models relates to attempts to test stem cell therapies for retinal degeneration. The mouse retina does not have a macula and it is rod-dominant and anatomically different from that of humans. Therefore, the pig is the more preferable species to use as a model for this particular application . Advantages of using large animal species to model several other human disease conditions have been reported.

Large animal species have a significant role in establishing the safety of stem cell applications, since the dosages of biologics, the route of administration, and treatment outcomes can be extrapolated readily to humans. The same is true for the development of procedures and techniques, such as surgical and visualization technologies, which will assist stem cell applications in the clinic. Non-invasive monitoring is required to guide cell injection; to observe cell survival, activation, and differentiation; and to evaluate off-target effects, cell persistence, and efficacy of engraftment. This information can be obtained by advanced anatomical and functional imaging techniques that will improve therapy in animal models, leading to clinical applications. Imaging technology and equipment, such as the micro-PET imaging system that provides high sensitivity and spatial resolution, have been developed for small animals. This and similar technologies can be applied to large animals and humans, although modifications and improvements will be required. Current progress and available imaging techniques for use in dogs, pigs, sheep, goats, and non-human primates were recently reviewed.

Research studies support the importance of the use of scaffolds and other homing devices that will instruct and control stem cell behavior. These devices should have the appropriate size and should be developed and tested in an environment suitable for clinical applications, for which large animals are a better choice than rodents. Large animals also allow a more realistic set of estimates of the quality and cost-effectiveness of new treatments.

Among limitations of the use of large animal species for regenerative medicine are a relative absence of stable and well-characterized stem cell lines and protocols for their maintenance, differentiation and monitoring of cell status, and limited availability of species-specific anti bodies, expression microarrays, and other research reagents. Techniques to genetically manipulate these species are still in an early stage of development.