title: Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker.
abstract: The sinoatrial node (SAN) is the primary pacemaker of the heart and controls heart rate throughout life. Failure of SAN function due to congenital disease or aging results in slowing of the heart rate and inefficient blood circulation, a condition treated by implantation of an electronic pacemaker. The ability to produce pacemaker cells in vitro could lead to an alternative, biological pacemaker therapy in which the failing SAN is replaced through cell transplantation. Here we describe a transgene-independent method for the generation of SAN-like pacemaker cells (SANLPCs) from human pluripotent stem cells by stage-specific manipulation of developmental signaling pathways. SANLPCs are identified as NKX2-5-cardiomyocytes that express markers of the SAN lineage and display typical pacemaker action potentials, ion current profiles and chronotropic responses. When transplanted into the apex of rat hearts, SANLPCs are able to pace the host tissue, demonstrating their capacity to function as a biological pacemaker.
authors.affiliation: McEwen Centre for Regenerative Medicine and Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors.forename: Stephanie I
authors.initials: SI
authors.lastname: Protze
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.|Division of Cardiology and the Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: The Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Internal Medicine A, Rappaport Faculty of Medicine and Research Institute and Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Udi
authors.initials: U
authors.lastname: Nussinovitch
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.|Division of Cardiology and the Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Lily
authors.initials: L
authors.lastname: Ohana
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.|Division of Cardiology and the Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.affiliation: The Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Cardiology, Rappaport Faculty of Medicine and Research Institute and Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Gepstein
authors.affiliation: McEwen Centre for Regenerative Medicine and Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Keller
mesh_terms: D000200:Action Potentials / Q000502:physiology; D001683:Biological Clocks / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D005818:Genetic Engineering; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000502:physiology*; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology*