Rethinking Stem Cell Therapy for Cardiomyopathy in View of Mammalian Cardiac Regeneration Limits

Stem cell transplantation represents a promising approach to regenerative medical therapies for many disorders, including neurodegenerative, rheumatologic, digestive, orthopedic, hematologic and cardiovascular diseases. In the case of stem cell therapy for ischemic cardiomyopathy, this promise has been blunted by a lack of understanding of critical factors governing regeneration of adult human heart muscle. This review aims to (1) summarize the characteristics and types of stem cells used to treat cardiomyopathies; (2) to survey the results of clinical trials conducted with stem cells used to treat cardiomyopathies; and (3) to understand limitations of and obstacles to effective stem cell therapies for cardiomyopathies. Stem cells contribute both constitutive and paracrine functions, exemplified by their ability to replace damaged and destroyed cells and to secrete cytokines and chemokines, respectively. Cardiac regenerative capacity, while high in most fish, amphibians and newborn mammals, is extremely limited in adult mammals. Alterations in physiologic functions necessary to prevent destructive oxidation in endotherms forced a trade-off with tissue regenerative capacity in these animals. A review of 15 stem cell trials for ischemic cardiomyopathies supports conclusions based on these considerations and underscores the need to maximize stem cell delivery efficiency. Experimental approaches to achieve this objective are reviewed.