title: Irx4 Marks a Multipotent, Ventricular-Specific Progenitor Cell.
abstract: While much progress has been made in the resolution of the cellular hierarchy underlying cardiogenesis, our understanding of chamber-specific myocardium differentiation remains incomplete. To better understand ventricular myocardium differentiation, we targeted the ventricle-specific gene, Irx4, in mouse embryonic stem cells to generate a reporter cell line. Using an antibiotic-selection approach, we purified Irx4+cells in vitro from differentiating embryoid bodies. The isolated Irx4+cells proved to be highly proliferative and presented Cxcr4, Pdgfr-alpha, Flk1, and Flt1 on the cell surface. Single Irx4+ventricular progenitor cells (VPCs) exhibited cardiovascular potency, generating endothelial cells, smooth muscle cells, and ventricular myocytes in vitro. The ventricular specificity of the Irx4+population was further demonstrated in vivo as VPCs injected into the cardiac crescent subsequently produced Mlc2v+myocytes that exclusively contributed to the nascent ventricle at E9.5. These findings support the existence of a newly identified ventricular myocardial progenitor. This is the first report of a multipotent cardiac progenitor that contributes progeny specific to the ventricular myocardium. Stem Cells 2016;34:2875-2888.
authors: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors: Daryl O
authors: DO
authors: Nelson
authors: Department of Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA.|Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Pratik A
authors: PA
authors: Lalit
authors: Department of Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA.|Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Mitch
authors: M
authors: Biermann
authors: Department of Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA.|Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Yogananda S
authors: YS
authors: Markandeya
authors: Department of Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA.
authors: Deborah L
authors: DL
authors: Capes
authors: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors: Luke
authors: L
authors: Addesso
authors: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors: Gina
authors: G
authors: Patel
authors: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Tianxiao
authors: T
authors: Han
authors: University of Wisconsin Biotechnology Center, University of Wisconsin, Madison, Wisconsin, USA.
authors: Manorama C
authors: MC
authors: John
authors: University of Wisconsin Biotechnology Center, University of Wisconsin, Madison, Wisconsin, USA.|Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Patricia A
authors: PA
authors: Powers
authors: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Karen M
authors: KM
authors: Downs
authors: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|Department of Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA.|Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Timothy J
authors: TJ
authors: Kamp
authors: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors: Gary E
authors: GE
authors: Lyons
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D002999:Clone Cells; D047108:Embryonic Development; D042783:Endothelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006352:Heart Ventricles / Q000166:cytology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D009928:Organ Specificity; D059010:Single-Cell Analysis; D013997:Time Factors
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; C485534:Irx4 protein, mouse
keywords: Cardiac; Developmental biology; Differentiation; Embryonic stem cells; Progenitor cells; Stem cell transplantation