Novel Cytoprotective Strategies for Cardiac Progenitor Cells

The discovery of primitive cardiac stem-like cells with the ability for self-renewal and the capacity for differentiation into all cardiac cell lineages has completely changed the prevailing view of the heart as a static, terminally differentiated organ.1 Like virtually all somatic tissues, the adult heart harbors a pool of stem/progenitor cells responsible for the maintenance of organ cell homeostasis. In this new concept, cardiac stem cells take central stage in the maintenance of the cellular and functional integrity of the heart throughout a lifetime. Perturbation of the cardiac stem cell pool by premature senescence or cellular injury may thus result in inadequate replenishment of functionally competent cardiac cells and ultimately lead to the development of organ failure.2 Hence, an understanding of the mechanisms regulating this cardiac stem cell pool is pivotal for the investigation of cardiac injury and dysfunction and may offer opportunities to promote myocardial repair and regeneration following tissue injury. The obvious conceptual and therapeutic significance of cardiovascular stem cell biology has sparked an enormous interest in the study of resident cardiac stem/progenitor cells. Since the first identification of endogenous cardiac stem/ progenitor cells in adult hearts 6 years ago by Hierlihy et al,3 several independent laboratories have confirmed the existence of resident cardiac stem-like cells and characterized their cardiomyogenic potential in vitro and in vivo in mammalian as well as human hearts (reviewed previously4). The urgent need for a convenient methodology to identify and isolate putative cardiac stem cells prompted early studies to focus on their phenotypic characterization. Because the “stemness” of a cell is not linked to a single specific biological marker, combinations of different stem cell–associated cell surface markers (including c-kit [a tyrosine kinase receptor that binds to steel factor1] and stem cell antigen [Sca]-15), as well as stem cell–associated properties, have been used for their isolation. Other, cell surface marker– independent cell isolation strategies have used methodologies in which cardiac tissue fragments generate cellular tissue aggregates, or so called cardiospheres, that are enriched with stem-like cells6 or have taken advantage of the capacity of stem cells to efflux vital dyes such as Hoechst 33342.3,7–9 This unique Hoechst efflux phenomenon is mediated by the ATP-binding cassette (ABC) transporters Mdr1 and Abcg2 and has become a highly useful primary purification technique for the isolation of putative stem cells, or so-called side population (SP) cells (reviewed previously10). Although individual laboratories have reported significant discrepancies regarding the expression pattern of abovementioned markers in their putative cardiac stem cell population, each of these markers has been identified in cardiac cells with inherent cardiomyogenic potential, thereby suggesting that the phenotypic differences reported among laboratories may root in methodological variations or reflect the identification of cells at phenotypically different stages of development (Table). Whereas extensive work has focused on phenotypic characterization of cardiac stem cells, little is known about the factors regulating cardiac stem cell survival and function. In the heart, lifelong exposure to cardiotoxins, reactive oxygen species (ROS), and metabolic stress take their toll on the aging myocardium, leading to premature cardiac cell death and senescence.11 In this harsh environment, effective defense systems are essential, particularly for stem cells that are required to continuously proliferate and replenish dying cells. A common defense mechanism adopted by stem cells is their high expression of ABC membrane transporters.12 These proteins are characterized by expression of an ABC region that hydrolyzes ATP to support energy-dependent substrate exportation (eg, cytotoxins, DNA-binding dyes) against steep concentration gradients from the intrato the extracellular space. As mentioned above, this property defines the molecular basis of the SP phenotype in stem cells. SP cells isolated from myocardium qualify as cardiac stem/progenitor cells as they are clonogenic and multipotent in vitro and give raise to cardiomyocytes and coronary vessels in vivo.3,7–9 Similar to SP cells from other tissues, cardiac SP cells express the ABC subfamily G member 2 (Abcg2), also known as the breast cancer resistant protein (Bcrp1).7 Recent evidence from hematopoietic stem cells indicates that Abcg2 is involved in promoting cell survival and protection from environmental stressors, particularly under hypoxic conditions.13 In this issue of Circulation Research, Martin et al address for the first time the cytoprotective role of Abcg2 in skeletal muscle cells.14 Using a murine myocardial cryoinjury model, these authors demonstrate that resident Abcg2-expressing cardiac SP cells substantially increase in numbers following injury. Interestingly, this increase in cardiac SP cells was accompanied by increased Abcg2 transcript expression in The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Myocardial Research, Department of Biomedicine, and Division of Cardiology (O.P.), University Hospital Basel, Switzerland; and Cardiac Muscle Research Laboratory, Cardiovascular Division, Department of Medicine (R.L.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Correspondence to Dr Ronglih Liao, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB 431, Boston, MA 02115. E-mail [email protected] (Circ Res. 2008;102:998-1001.) © 2008 American Heart Association, Inc.