Cardiac Progenitor Cells: Potency and Control PAOLO DI NARDO, 1,2,3 * GIANCARLO FORTE, 1,2,3 ARTI AHLUWALIA, 4 AND MARILENA MINIERI 1,2,3 1 Dipartimento di Medicina Interna, Laboratorio di Cardiologia Molecolare e Cellulare, Universita` di Roma Tor Vergata, Roma, Italy 2 Istituto Nazionale per le Ricerche Cardiovascolari (INRC), Bologna, Italy 3 Japanese-Italian Tissue Engineering Laboratory (JITEL), Tokyo Women’s Medical University — Waseda University Joint Institution for Advanced Biomedical Sciences (TWIns), Tokyo, Japan 4 Centro Interdipartimentale di Ricerca ‘‘E. Piaggio’’, Universita` di Pisa, Italy Stem cell-based regeneration of the heart has focused much scientific and public attention being cardiac diseases the major cause of disability and death in industrialized countries. Innumerable efforts have been taken to unveil the mechanisms undergoing stem cell proliferation and fate, but much remains to be endeavoured for their application in clinical practice. Nevertheless, the discovery of progenitor cells resident within the cardiac tissue has sparked off enthusiasm about the possibility of efficiently and safely engineering them to repair the injured myocardium. Indeed, the early applications of the cardiac progenitor cells, mostly based on simplistic concepts and techniques, have failed highlighting the prerequisite of expanding the knowledge about progenitor cell features and microenvironmental conditioning. In this review, recent information on resident cardiac progenitor cells has been systematically gathered in order to create a valuable instrument to support investigators in their efforts to establish an efficient cardiac cell therapy. J. Cell. Physiol. 224: 590–600, 2010. ß 2010 Wiley-Liss, Inc. The prowess of stem cells to repair tissues hit by degenerative disorders has sparked off universal interest, as no other medical achievement in the history of mankind. Nonetheless, the innumerable efforts so far endeavored worldwide have not brought the possibility of repairing most of solid tissues and organs by administering stem cells to fruition. Indeed, several aspects of the basic knowledge and related technological processes still remain uncertain hampering the efficient and safe application of stem cells in clinical practice. So far the strategies adopted to maximize the in vivo rejuvenating capacity by the rare adult stem cells identified in human organs, such as bone marrow (Heissig et al., 2005), heart (Quaini et al., 2002), brain (Watts et al., 2005), skin (Tumbar et al., 2004), eyes (Lavker et al., 2004), gastrointestinal tract (Brittan and Wright, 2002), liver (Guettier, 2005), pancreas (Seaberg et al., 2004), lungs (Liu et al., 2004), breast (Woodward et al., 2005), ovaries, prostate, and testis (Blau et al., 2001) have proved quite futile. A decade of intensive and highly funded research has neither led to the identification of the differentiating potential of the diverse stem cell populations nor of the critical array of factors required to generate a specific cell phenotype. On the other hand, techniques to characterize stem cells in vitro, and then implant them and promote their engraftment into damaged organs as well as protocols to by-pass the natural regenerative limits of stem cells are still unsafe and inefficient. In spite of this contingency, some institutions were not dissuaded from establishing clinical centers to offer ethically questionable ‘‘miraculous’’ treatments to otherwise incurable patients. It goes without saying that, since cardiac diseases remain the first cause of death in industrialized countries notwithstanding the continuous advancements in their treatment, stem cell-based regeneration of the heart has elicited much scientific and public attention, but has also inflated a potent commercial concern. Current post-infarction myocardial revascularization protocols include the administration of mesenchymal stem cells, either by intravascular or intramyocardial injection, without clear scientific background and in spite of the frustrating results of several controlled clinical trials (Fischer-Rasokat et al., 2009; Menasche ´, 2009). Cells injected into damaged hearts are cell populations roughly isolated from the bone marrow of the same patient and the supposed improvements in the cardiac performance could be related to their potential paracrine effects and/or myocardial neovascularization. Indeed, the types of cells suitable for heart regeneration in man remain to be defined (Murry et al., 2004). Moreover, generating new cardiomyocytes may be not sufficient to efficiently repair the texture of the myocardial tissue, which also includes fibroblasts, smooth muscle cells, endothelial cells and adipocytes, among others. In healthy human hearts, only 10–20% of the cell complex constituting the whole organ are cardiomyocytes (Oh et al., 2003; Smith et al., 2007) and, at the age of 25 years, no more than 1% of them are annually substituted by progenitor cells, with the percentage reducing to less than 0.5% at the age of 75. In total, less than 50% of cardiomyocytes are renewed during a normal human life span (Bergmann et al., 2009). In addition, it is likely that there is a natural limitation to progenitor cell capability to repair injured myocardium, considering that infarction as well as widespread myocardial diseases progress to fibrosis and not to newly generated contractile tissue. Nevertheless, features so far documented in reliably isolated and manipulated progenitor cells resident within the cardiac tissue (cardiac progenitor cells, CPC), although fragmentary and often controversial, do suggest that innovative treatments to repair damaged myocardium could have promising clinical applications. However, as a prerequisite, a collective effort must be made to identify the basic biological cues and to define technical and scientific milestones towards an Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript. *Correspondence to: Paolo Di Nardo, Dipartimento di Medicina Interna, Laboratorio di Cardiologia Molecolare e Cellulare, Universita ` di Roma Tor Vergata, Via Montpellier, 1, 00133 Roma, Italy. E-mail: dinardo@uniroma2.it Received 15 January 2010; Accepted 4 March 2010 Published online in Wiley InterScience (www.interscience.wiley.com.), 4 May 2010. DOI: 10.1002/jcp.22165 REVIEW ARTICLE 590 Journal of Journal of Cellular Physiology Cellular Physiology ß 2010 WILEY-LISS, INC.