Large animal models for cardiac stem cell therapies

Abstract

Cardiovascular disease is the leading cause of death in developed countries and is one of the leading causes of disease burden in developing countries. Therapies have markedly increased survival in several categories of patients, nonetheless mortality still remains high. For this reason high hopes are associated with recent developments in stem cell biology and regenerative medicine that promise to replace damaged or lost cardiac muscle with healthy tissue, and thus to dramatically improve the quality of life and survival in patients with various cardiomyopathies. Much of our insight into the molecular and cellular basis of cardiovascular biology comes from small animal models, particularly mice. However, significant differences exist with regard to several cardiac characteristics when mice are compared with humans. For this reason, large animal models like dog, sheep and pig have a well established role in cardiac research. A distinct characteristic of cardiac stem cells is that they can either be endogenous or derive from outside the heart itself; they can originate as the natural course of their differentiation programme (e.g., embryonic stem cells) or can be the result of specific inductive conditions (e.g., mesenchymal stem cells). In this review we will summarize the current knowledge on the kind of heart-related stem cells currently available in large animal species and their relevance to human studies as pre-clinical models.

Isolation, Characterization and Differentiation Potential of Cardiac Progenitor Cells in Adult Pigs

“…However, significant differences exist with regard to several cardiac characteristics when mice are compared with humans (Table 1) (Gandolfi et al 2011;Dixon et al 2009). An important parameter is heart rate, with an adult mouse heart beating 500-600 times per minute, compared with the 60-100 times typical of the human.…”

“…fact, has been widely used as a model in cardiovascular research (Guiney et al 1965;Bustad and McClellan 1966;Douglas et al 1972;Hughes et al 1986) and, over the past decade, swine have been increasingly used in studies of chronic ischemia because of their numerous similarities to humans ( Table 2. Comparison of indicative anatomy and physiology data between the pig, the human and the mouse (Gandolfi et al 2011) (Appendix a).…”

Transplantation and Tracking of Human-Induced Pluripotent Stem Cells in a Pig Model of Myocardial Infarction

“…12 Although some of these issues can be addressed in vitro or in appropriate small-animal models, others will require exploration in large-animal models, which are more similar to humans. 13 Transplanted human cardiomyocytes, for example, are unlikely to fully functionally integrate with rodent myocardium because of highly dissimilar beating rates. 11 Therefore, meaningful assessment of human cells for heart repair must be demonstrated in large-animal models such as dogs, pigs, or monkeys.…”

“…11 Therefore, meaningful assessment of human cells for heart repair must be demonstrated in large-animal models such as dogs, pigs, or monkeys. 13 Clearly, advanced imaging technologies allowing for longitudinal tracking of cellular grafts and ideally enabling monitoring of donor cell survival, proliferation, distribution, or even differentiation are crucial for (pre)clinical evaluation of novel cellbased therapeutics. 14 At present, transgene-based imaging approaches that fulfill these requirements are mainly restricted to far-red fluorescence reporters or photon-emitting technologies, in particular those based on luciferase expression.…”

Invasive assessment of the coronary microcirculation using the index of microcirculatory resistance: Description and validation of an animal model

“…Pigs are the most suitable since their cardiac vascularization, coronary anatomy, and poor subendocardial to epicardial collateral network are similar to humans. 8,9 A key step in the assessment of IMR is induction of maximal hyperemia. This is achieved by vasodilation of the entire coronary tree using drugs with vasodilatory effects on small vessels, of which intravenous adenosine and intracoronary papaverine are the most effective.…”