Cardiac progenitor cells: the revolution continues.

In the last few years we have witnessed one of most extraordinary revolutions in cardiovascular medicine, namely, an explosion of basic and clinical studies that support the notion that the diseased heart can be repaired by administration of stem cells, resulting in formation of functional new myocytes and vessels. Although the mechanism by which cell therapy improves cardiac function and anatomy remains uncertain, translation of basic findings to the clinical setting is proceeding at a feverish pace.1 A multitude of small, mostly nonrandomized clinical studies have reported improvement in cardiac perfusion and function after therapy with various cell types in patients with acute myocardial infarction or chronic ischemic cardiomyopathy.1 Larger, randomized, double-blinded studies will be reported soon; if they confirm the salubrious effects of cell-based therapies observed in the initial trials, our management of acute myocardial infarction and heart failure will change dramatically. One of the most important and unresolved issues in this scenario is the identity of the ideal cell for myocardial reconstitution. Although most of the clinical studies reported to date have used bone marrow– or skeletal muscle–derived cells, a host of other cells are being investigated in the experimental laboratory. Among these, resident cardiac stem cells (CSCs), discovered by Anversa’s group in 2003,2 hold great promise. In their initial report,2 Beltrami et al identified a lin /c-kit population of primitive cells that can be clonally expanded, differentiates into cardiac myocytes, smooth muscle cells, and endothelial cells in vitro, and is able to reconstitute infarcted myocardium in vivo. It is of translational interest that these cells can effect cardiac repair when delivered via the intravascular route.3 CSCs have also been shown to be present in the human heart, where they give rise to new myocytes in patients with aortic stenosis4 and ischemic cardiomyopathy.5 Because CSCs are normal components of the adult heart and appear to be responsible for the physiologic and pathologic turnover of cardiac myocytes and non-myocytes, they may be particularly suitable for reconstituting dead myocardium. In addition to CSCs, over the past 2 years several other populations of cardiac primitive cells have been described that are able to differentiate into cardiomyocytes or regenerate infarcted myocardium or both. In 2003, Oh et al6 identified Sca-1 cardiac progenitors that expressed CD31 but not c-kit or other markers of hematopoietic or endothelial progenitors. When injected intravenously into a mouse with myocardial infarction, these cells were able to generate cardiomyocytes, both with and without cell fusion. These cells differ from those described by Beltrami et al2 in that they consistently express Sca-1 but not c-kit; they also differ from the cells described by Pfister et al7 (see below) in that they express CD31. In 2004, Messina et al8 reported the formation of cardiospheres from human and murine hearts that expressed Sca-1, c-kit, KDR/flk-1, and CD31. These cardiospheres were clonogenic in vitro and repaired infarcted mouse hearts in vivo. A detailed characterization of these proliferating cardiospheres grown in vitro from human endocardial biopsies revealed that they are positive for c-kit, MDR1, connexin 43, and the cardiac transcription factor Nkx2–5.9 Also in 2004, Martin et al10 reported the identification of an Abcg2-expressing cardiac SP cell population from embryonic as well as adult mouse hearts that are capable of proliferation and differentiation into a cardiomyocytic phenotype. Interestingly, these CSPs were negative for CD31.10 In 2005, Pfeister et al7 described a pool of cardiac primitive cells that were identified by their ability to efflux the Hoechst 33342 dye (a property similar to that of cells identified in other organs and termed side-population [SP] cells; this property is attributable to expression of ATPbinding cassette transporters). These cardiac SP cells (CSPs) were found to be Sca-1 /CD31 , to differentiate into cardiomyocytes in vitro, and to possess the properties of stem cells (self-renewal and clonogenicity).7 In 2005, Laugwitz et al11 reported yet another primitive cell population in the heart that expressed the transcription factor isl1 but did not extrude Hoechst 33342 and did not express c-kit. These cells exhibited a cardiomyocytic phenotype when cocultured with neonatal cardiomyocytes in vitro and showed electrical as well as contractile properties reminiscent of neonatal cardiomyocytes.11 Despite these findings, however, the isl1-positive cells described by Laugwitz et al cannot be regarded as cardiac stem cells until they are shown to be multipotent. Furthermore, the cells studied by Laugwitz et al were isolated from neonatal hearts; it is unknown whether cells with the same properties can be isolated from the adult heart as well (a critical issue from the standpoint of therapeutic application). In fact, isl1-positive cells have not been described in the adult left ventricle, with the possible exception of the outflow tract. Moreover, isl1-positive cells have not been shown to be able repair the infarcted heart or to regenerate cardiac tissue in vivo. In view of these considerThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Institute of Molecular Cardiology, University of Louisville, Ky. Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail [email protected] (Circ Res. 2005;97:1080-1082.) © 2005 American Heart Association, Inc.