title: Expression of coxsackievirus and adenovirus receptor separates hematopoietic and cardiac progenitor cells in fetal liver kinase 1-expressing mesoderm.
abstract: In developing embryos or in vitro differentiation cultures using pluripotent stem cells (PSCs), such as embryonic stem cells and induced pluripotent stem cells, fetal liver kinase 1 (Flk1)-expressing mesodermal cells are thought to be a heterogeneous population that includes hematopoietic progenitors, endothelial progenitors, and cardiac progenitors. However, information on cell surface markers for separating these progenitors in Flk1⁺ cells is currently limited. In the present study, we show that distinct types of progenitor cells in Flk1⁺ cells could be separated according to the expression of coxsackievirus and adenovirus receptor (CAR, also known as CXADR), a tight junction component molecule. We found that mouse and human PSC- and mouse embryo-derived Flk1⁺ cells could be subdivided into Flk1⁺CAR⁺ cells and Flk1⁺CAR⁻ cells. The progenitor cells with cardiac potential were almost entirely restricted to Flk1⁺CAR⁺ cells, and Flk1⁺CAR⁻ cells efficiently differentiated into hematopoietic cells. Endothelial differentiation potential was observed in both populations. Furthermore, from the expression of CAR, Flk1, and platelet-derived growth factor receptor-α (PDGFRα), Flk1⁺ cells could be separated into three populations (Flk1⁺PDGFRα⁻ CAR⁻ cells, Flk1⁺PDGFRα⁻CAR⁺ cells, and Flk1⁺PDGFRα⁺CAR⁺ cells). Flk1⁺PDGFRα⁺ cells and Flk1⁺PDGFRα⁻ cells have been reported as cardiac and hematopoietic progenitor cells, respectively. We identified a novel population (Flk1⁺PDGFRα⁻ CAR⁺ cells) with the potential to differentiate into not only hematopoietic cells and endothelial cells but also cardiomyocytes. Our findings indicate that CAR would be a novel and prominent marker for separating PSC- and embryo-derived Flk1⁺ mesodermal cells with distinct differentiation potentials.
authors.affiliation: Laboratory of Stem Cell Regulation and Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Laboratory of Biochemistry and Molecular Biology, iPS Cell-Based Research Project on Hepatic Toxicity and Metabolism, and Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Tashiro
authors.affiliation: Laboratory of Stem Cell Regulation and Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Laboratory of Biochemistry and Molecular Biology, iPS Cell-Based Research Project on Hepatic Toxicity and Metabolism, and Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan.
authors.forename: Nobue
authors.initials: N
authors.lastname: Hirata
authors.affiliation: Laboratory of Stem Cell Regulation and Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Laboratory of Biochemistry and Molecular Biology, iPS Cell-Based Research Project on Hepatic Toxicity and Metabolism, and Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan.
authors.forename: Atsumasa
authors.initials: A
authors.lastname: Okada
authors.affiliation: Laboratory of Stem Cell Regulation and Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Laboratory of Biochemistry and Molecular Biology, iPS Cell-Based Research Project on Hepatic Toxicity and Metabolism, and Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of Stem Cell Regulation and Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Laboratory of Biochemistry and Molecular Biology, iPS Cell-Based Research Project on Hepatic Toxicity and Metabolism, and Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Laboratory of Stem Cell Regulation and Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Laboratory of Biochemistry and Molecular Biology, iPS Cell-Based Research Project on Hepatic Toxicity and Metabolism, and Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Laboratory of Stem Cell Regulation and Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Laboratory of Biochemistry and Molecular Biology, iPS Cell-Based Research Project on Hepatic Toxicity and Metabolism, and Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan kawabata@nibio.go.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawabata
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011991:Receptors, Virus / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D011991:Receptors, Virus; C085301:adenovirus receptor; C105941:coxsackievirus B receptor
keywords: Cardiomyocytes; Coxsackievirus and adenovirus receptor; Differentiation; Fetal liver kinase 1; Hematopoietic cells; Mesoderm