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(Circulation Research. 2008;103:825.)
© 2008 American Heart Association, Inc.

Cellular Biology

Role of the ATP-Binding Cassette Transporter Abcg2 in the Phenotype and Function of Cardiac Side Population Cells

Otmar Pfister^*, Angelos Oikonomopoulos^*, Konstantina-Ioanna Sereti^*, Regina L. Sohn, Darragh Cullen, Gabriel C. Fine, Frédéric Mouquet, Karen Westerman, Ronglih Liao

From the Cardiac Muscle Research Laboratory (O.P., A.O., K.-I.S., R.L.S., D.C., G.C.F., F.M., R.L.), Cardiovascular Division, Department of Medicine; and Department of Anesthesia (K.W.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; School of Medicine (A.O., K.-I.S.), University of Crete, Greece; and University of Washington School of Medicine (G.C.F.), Seattle. Present address for O.P.: Myocardial Research, Department of Biomedicine, and Division of Cardiology, University Hospital Basel, Switzerland. Present address for F.M.: Cardiologie C, Lille University Hospital, France.

Correspondence to Dr Ronglih Liao, Division of Cardiology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB 431, Boston, MA 02115. E-mail rliao{at}rics.bwh.harvard.edu

Recently, the side population (SP) phenotype has been introduced as a reliable marker to identify subpopulations of cells with stem/progenitor cell properties in various tissues. We and others have identified SP cells from postmitotic tissues, including adult myocardium, in which they have been suggested to contribute to cellular regeneration following injury. SP cells are identified and characterized by a unique efflux of Hoechst 33342 dye. Abcg2 belongs to the ATP-binding cassette (ABC) transporter superfamily and constitutes the molecular basis for the dye efflux, hence the SP phenotype, in hematopoietic stem cells. Although Abcg2 is also expressed in cardiac SP (cSP) cells, its role in regulating the SP phenotype and function of cSP cells is unknown. Herein, we demonstrate that regulation of the SP phenotype in cSP cells occurs in a dynamic, age-dependent fashion, with Abcg2 as the molecular determinant of the cSP phenotype in the neonatal heart and another ABC transporter, Mdr1, as the main contributor to the SP phenotype in the adult heart. Using loss- and gain-of-function experiments, we find that Abcg2 tightly regulates cell fate and function. Adult cSP cells isolated from mice with genetic ablation of Abcg2 exhibit blunted proliferation capacity and augmented cell death. Conversely, overexpression of Abcg2 is sufficient to enhance cell proliferation, although with a limitation of cardiomyogenic differentiation. In summary, for the first time, we reveal a functional role for Abcg2 in modulating the proliferation, differentiation, and survival of adult cSP cells that goes beyond its distinct role in Hoechst dye efflux.

Key Words: Abcg2 • Mdr1 • progenitor cells • proliferation • SP cells

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