ARTICLE www.nature.com/clinicalpractice/cardio Plasticity and cardiovascular applications of multipotent adult progenitor cells Beatriz Pelacho, Xabier L Aranguren, Manuel Mazo, Gloria Abizanda, Juan José Gavira, Carlos Clavel, Maria Gutierrez-Perez, Aernout Luttun, Catherine M Verfaillie and Felipe Prósper* INTRODUCTION Every year in Europe and the US, approximately 550,000 people die of disease related to cardiac cell death. 1 The fundamental mechanism leading to the high morbidity and mortality in patients with any form of coronary artery disease is isch- emia that induces myocardial injury and subse- quent cardiomyocyte loss. Although the existence of cardiac progenitor cells has been reported and suggested to indicate a certain regeneration capacity, 2,3 adult myocardium—unlike skeletal muscle—does not show substantial regeneration after ischemic or other injury. Consequently, cardiomyocyte loss due to disease or injury is irreversible and typically results in the replace- ment of working cardiac tissue with nonfunc- tional scar tissue. Compensatory hypertrophy of the myocardium can, to a limited degree, alleviate the loss of contractile function that accompanies scar formation. Myocardial hypertrophy, however, predisposes the heart to arrhythmia, which frequently results in ventricular fibrillation and sudden death. 4,5 EXISTING APPROACHES FOR CARDIAC REGENERATION Currently, cardiac transplantation is the only curative therapeutic option for patients with severely diseased hearts. The ability to replace or regenerate damaged myocardium with functional, coupled cardiomyocytes would have obvious therapeutic value. To accomplish these effects, several approaches are actively being pursued by various research groups. Some work is focused on the in vivo manipulation of pre-existing cardiac cells, such as through inducing cardiomyocytes to reenter the cell cycle in vivo, 6 promoting cardiac cell migration and survival through the activa- tion of antiapoptotic proteins (e.g. Akt), 7,8 and identifying genes that are able to initiate a cardio- myogenic differentiation, with the hope of being able to transdifferentiate cardiac fibroblasts into cardiomyocytes. 9 Most groups are focused on the transplanta- tion of new cells into a diseased heart, with the Cardiovascular disease is the leading cause of death worldwide, which has encouraged the search for new therapies that enable the treatment of patients in palliative and curative ways. In the past decade, the potential benefit of transplantation of cells that are able to substitute for the injured tissue has been studied with several cell populations, such as stem cells. Some of these cell populations, such as myoblasts and bone marrow cells, are already being used in clinical trials. The laboratory of CM Verfaillie has studied primitive progenitors, termed multipotent adult progenitor cells, which can be isolated from adult bone marrow. These cells can differentiate in vitro at the single-cell level into functional cells that belong to the three germ layers and contribute to most, if not all, somatic cell types after blastocyst injection. This remarkably broad differentiation potential makes this particular cell population a candidate for transplantation in tissues in need of regeneration. Here, we focus on the regenerative capacity of multipotent adult progenitor cells in several ischemic mouse models, such as acute and chronic myocardial infarction and limb ischemia. KEYWORDS cardiovascular regeneration, ischemia, multipotent adult progenitor cells (MAPCs) B Pelacho is an investigator at the Foundation for Applied Medical Research, University of Navarra. XL Aranguren, M Mazo, and M Gutierrez-Perez are PhD students, G Abizanda is a research associate, and F Prósper is Director of Hematology and Cell Therapy and an investigator in the Division of Cancer, Foundation for Applied Medical Research, University of Navarra, Pamplona, and JJ Gavira is a cardiologist in the Cardiology Department at the University of Navarra, Pamplona, Spain. C Clavel is postdoctoral researcher and CM Verfaillie is Director of the Stem Cell Instituut Leuven, KU Leuven, Leuven, Belgium. A Luttun is an investigator in the Vasculogenesis Unit at the Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium. Correspondence *Hematology and Cell Therapy, Clinica Universitaria, Av Pio XII 36, Pamplona 31008, Spain fprosper@unav.es Received 20 July 2006 Accepted 1 November 2006 www.nature.com/clinicalpractice doi:10.1038/ncpcardio0735 SUMMARY FEBRUARY 2007 VOL 4 SUPPLEMENT 1 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE S15