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

Abstract

Abstract-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. Key Words: Abcg2 Ⅲ Mdr1 Ⅲ progenitor cells Ⅲ proliferation Ⅲ SP cells R ecently, 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 including the heart. 1 On the molecular level, the SP phenotype is linked to the presence of ATP-binding cassette (ABC) transporters with the ability to efficiently efflux the DNA binding dye Hoechst 33342. 2 This ABC transporterdependent Hoechst efflux phenomenon confers the characteristic fluorescent-activated cell sorting (FACS) profile of SP cells as a Hoechst-low "side population" located to the periphery of the Hoechst-high main population. 2 Among the various members of the ABC transporter superfamily, Abcg2 (also referred to as breast cancer resistance protein 1 [Bcrp1]) and Mdr1 (also referred to as P-glycoprotein [p-gp] or Abcb1) have been shown to efficiently efflux Hoechst 33342 and thereby confer the SP phenotype. 3 Although both transporters are highly expressed in bone marrow (BM)SP cells, studies performed in mice with targeted disruption of the Mdr1a and Mdr1b genes, the murine homologs of the human Abcb1/Mdr1 gene, demonstrated that Abcg2 is the sole molecular determinant of the SP phenotype in hematopoietic stem cells. 4 Moreover, Abcg2 expression is conserved in SP cells from a wide range of tissues including blood, gonad, lung, skeletal muscle and the retina, suggesting an important role of Abcg2 in stem cells. 4 -7 We and others have characterized SP cells isolated from adult myocardium. 8 -11 These cardiac (c)SP cells are phenotypically distinct from BMSP cells, in that they are not hematopoietic but exhibit the potential to differentiate into functional cardiomyocytes. 10 As in SP cells from the bone marrow, Abcg2 is expressed in SP cells from the heart. 9 The contribution of Abcg2 to the cSP phenotype and its biological significance in cSP progenitor cells, however, remain unknown. In this study, we find that the contribution of Abcg2 to the SP phenotype in the heart exists in an age-dependent manner, with Abcg2 as the molecular determinant of the SP phenotype in the neonatal heart and Mdr1 as the basis for the SP phenotype in the adult heart. In addition, we demonstrate Original

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…This unique property is mediated through the action of the ATP-binding cassette transporter proteins ABCG2 (Zhou et al, 2001) and Abcb1/Mdr1 (Pfister et al, 2008) expressed on the cell surface. SP cells with stem cell-like properties in adult hearts were first reported by Hierlihy et al (2002).…”

“…Recent studies indicate that ABCG2 is important for cytoprotection and for regulating the function and homeostasis of CSP cells. Using a loss-and gain-of-function strategy, Pfister et al (2008) demonstrated that adult CSP cells isolated from ABCG2 knockout mice exhibited a blunted proliferation capacity, leading to increased cell death. In contrast, overexpression of ABCG2 significantly enhanced CSP cell proliferation but limited their capacity for cardiomyogenic differentiation.…”

Endogenous retinoic acid regulates cardiac progenitor differentiation

“…Two ABC transporter superfamily members, Abcg2 and Multidrug resistance (Mdr)1, drive Hoechst dye efflux, and by their differentially enriched expression in stem cells constitute the probable basis of the SP phenotype. Genetic studies indicate that Abcg2 regulates the proliferative capacity and survival of the adult cardiac SP (35). Enriched Abcg2 expression in embryonic and fetal hearts suggests that this transporter also plays a prominent role during cardiac development (18).…”

Scutellaria Extract Decreases the Proportion of Side Population Cells in a Myeloma Cell Line by Down-regulating the Expression of ABCG2 Protein

“…The efflux of Hoechst dye is attributed to members of the ABC family of membrane pumps, with ABCG2 and ABCB1 identified as likely mediators of Hoechst efflux (Pfister et al, 2008;Dean et al, 2009). ABCG2 protein plays an important role DOI:http://dx.doi.org/10.7314/APJCP.2013.14.12 in the drug resistance of normal stem cells and tumor stem cells, and is a molecular determinant of the SP phenotype (Zhou et al, 2001;Dean et al, 2009).…”